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  • 1.
    Andersen, Peter M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Binzer, M.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Nilsson, P.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Ala-Hurula, V.
    Keränen, M.-L.
    Bergmark, L.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurofysiologi.
    Saarinen, A.
    Haltia, T.
    Tarvainen, I.
    Kinnunen, E.
    Udd, B.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation: a clinical and genealogical study of 36 patients1996Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 119, s. 1153-1172Artikel i tidskrift (Refereegranskat)
  • 2.
    Andersen, Peter M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Hempel, Maja
    Santer, René
    Nordström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Tsiakas, Konstantinos
    Johannsen, Jessika
    Volk, Alexander E.
    Bierhals, Tatjana
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Phenotype in an Infant with SOD1 Homozygous Truncating Mutation2019Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, nr 5, s. 486-488Artikel i tidskrift (Refereegranskat)
  • 3.
    Andersen, Peter M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, P.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    CuZn-superoxide dismutase, extracellular superoxide dismutase, and glutathione peroxidase in blood from individuals homozygous for ASP90ALA CuZn-superoxide dismutase mutation1998Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 70, nr 2, s. 715-720Artikel i tidskrift (Refereegranskat)
  • 4.
    Andersen, Peter M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, P.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Keränen, M.-L.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Hägglund, J.
    Karlsborg, M.
    Ronnevi, L.-O.
    Gredal, O.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia1997Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 120, nr 10, s. 1723-1737Artikel i tidskrift (Refereegranskat)
  • 5.
    Andersen, Peter M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Ala-Hurula, Veli
    Keränen, Marja-Leena
    Tarvainen, Ilkka
    Haltia, Tuula
    Nilsson, Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Binzer, Michael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase1995Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 10, s. 61-66Artikel i tidskrift (Refereegranskat)
  • 6.
    Antonyuk, Svetlana V
    et al.
    Molecular Biophysics Group, School of Biological Sciences, University of Liverpool.
    Strange, Richard W
    Molecular Biophysics Group, School of Biological Sciences, University of Liverpool.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Hasnain, S Samar
    Molecular Biophysics Group, School of Biological Sciences, University of Liverpool.
    The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding2009Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 388, nr 2, s. 310-326Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Extracellular superoxide dismutase (SOD3) is a homotetrameric copper- and zinc-containing glycoprotein with affinity for heparin. The level of SOD3 is particularly high in blood vessel walls and in the lungs. The enzyme has multiple roles including protection of the lungs against hyperoxia and preservation of nitric oxide. The common mutation R213G, which reduces the heparin affinity of SOD3, is associated with increased risk of myocardial infarctions and stroke. We report the first crystal structure of human SOD3 at 1.7 A resolution. The overall subunit fold and the subunit-subunit interface of the SOD3 dimer are similar to the corresponding structures in Cu-Zn SOD (SOD1). The metal-binding sites are similar to those found in SOD1, but with Asn180 replacing Thr137 at the Cu-binding site and a much shorter loop at the zinc-binding site. The dimers form a functional homotetramer that is fashioned through contacts between two extended loops on each subunit. The N- and C-terminal end regions required for tetramerisation and heparin binding, respectively, are highly flexible. Two grooves fashioned by the tetramer interface are suggestive as the probable sites for heparin and collagen binding.

  • 7.
    Bergemalm, Daniel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jonsson, P Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Graffmo, Karin S
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Changes in the spinal cord proteome of an amyotrophic lateral sclerosis murine model determined by differential in-gel electrophoresis2009Ingår i: Molecular and cellular proteomics, ISSN 1535-9484, Vol. 8, nr 6, s. 1306-1317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons resulting in progressive paralysis. To date, more than 140 different mutations in the gene encoding CuZn-superoxide dismutase (SOD1) have been associated with ALS. Several transgenic murine models exist in which various mutant SOD1s are expressed. We have used differential in-gel electrophoresis (DIGE) to analyze the changes in the spinal cord proteome induced by expression of the unstable SOD1 truncation mutant G127insTGGG (G127X) in mice. Unlike mutants used in most other models, G127X lacks SOD activity and is present at low levels, thus reducing the risk of overexpression artifacts. The mice were analyzed at their peak body weights, just before onset of symptoms. Variable importance plot (VIP) analysis showed that 420 of 1,800 detected protein spots contributed significantly to the differences between the groups. By MALDI-TOF MS analysis, 54 proteins were identified. One spot was found to be a covalently linked mutant SOD1 dimer, apparently analogous to SOD1 immunoreactive bands migrating at double the molecular weight of SOD1 monomers previously detected in humans and mice carrying mutant SOD1s and in sporadic ALS cases. Analyses of affected functional pathways, and the subcellular representation of alterations suggest that the toxicity exerted by mutant SODs induces oxidative stress and affects mitochondria, cellular assembly/organization, and protein degradation.

  • 8.
    Bergemalm, Daniel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Srivastava, Vaibhav
    Graffmo, Karin S
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wingsle, Gunnar
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice2010Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 114, nr 2, s. 408-418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutant superoxide dismutase-1 (SOD1) causes amyotrophic lateral sclerosis (ALS) through a cytotoxic mechanism of unknown nature. A hallmark in ALS patients and transgenic mouse models carrying human SOD1 (hSOD1) mutations are hSOD1-immunoreactive inclusions in spinal cord ventral horns. The hSOD1 inclusions may block essential cellular functions or cause toxicity through sequestering of other proteins. Inclusions from four different transgenic mouse models were examined after density gradient ultracentrifugation. The inclusions are complex structures with heterogeneous densities and are disrupted by detergents. The aggregated hSOD1 was mainly composed of subunits that lacked the native stabilizing intra-subunit disulfide bond. A proportion of subunits formed hSOD1 oligomers or was bound to other proteins through disulfide bonds. Dense inclusions could be isolated and the protein composition was analyzed using proteomic techniques. Mutant hSOD1 accounted for half of the protein. Ten other proteins were identified. Two were cytoplasmic chaperones, four were cytoskeletal proteins, and 4 were proteins that normally reside in the endoplasmic reticulum (ER). The presence of ER proteins in inclusions containing the primarily cytosolic hSOD1 further supports the notion that ER stress is involved in ALS.

  • 9.
    Bergh, Johan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Graffmo, Karin Sixtensdotter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Jonsson, P. Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Lang, Lisa
    Stockholm, Sweden.
    Danielsson, Jens
    Stockholm, Sweden.
    Oliveberg, Mikael
    Stockholm, Sweden.
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping2015Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 14, s. 4489-4494Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease.

  • 10.
    Birve, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Neuwirth, Christoph
    Weber, Markus
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nilsson, Ann-Charloth
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Jonsson, Per Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis2010Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, nr 21, s. 4201-4206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reported.

  • 11. Brotherton, Terrell
    et al.
    Polak, Meraida
    Kelly, Crystal
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Andersen, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Glass, Jonathan D
    A novel ALS SOD1 C6S mutation with implications for aggregation related toxicity and genetic counseling2011Ingår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 12, nr 3, s. 215-219Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this report we describe an ALS family with a novel missense SOD1 mutation with substitution of serine for cysteine at the sixth amino acid (C6S). This mutation has interesting implications for the role of disulfides in causing disease. After identification of the ALS proband, we examined 17 members of an extended family and performed DNA mutation analysis on 21 family members. The level and activity of SOD1 in C6S carriers and wild-type family members was analyzed in erythrocytes. We found that the C6S mutation results in disease with an autosomal dominant mode of inheritance and markedly reduced penetrance. The S6 mutated protein demonstrates high stability relative to the C6 wild-type protein. The specific dismutation activity of S6 SOD1 is normal. In conclusion, C6S is a novel FALS associated mutation with reduced disease penetrance, long survival time and a phenotype very different from the other SOD1 mutations reported in codon C6. This mutation may provide insight into the role of SOD1 structural changes in disease.

  • 12.
    Bruce, Stephen J
    et al.
    Umeå Plant Science Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cloarec, Olivier
    Technologie Servier, 45000 Orleans, France.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Moritz, Thomas
    Umeå Plant Science Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Evaluation of a protocol for metabolic profiling studies on human blood plasma by combined ultra-performance liquid chromatography/mass spectrometry: From extraction to data analysis2009Ingår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 372, nr 2, s. 237-249Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The investigation presented here describes a protocol designed to perform high-throughput metabolic profiling analysis on human blood plasma by ultra-performance liquid chromatography/mass spectrometry (UPLC/MS). To address whether a previous extraction protocol for gas chromatography (GC)/MS-based metabolic profiling of plasma could be used for UPLC/MS-based analysis, the original protocol was compared with similar methods for extraction of low-molecular-weight compounds from plasma via protein precipitation. Differences between extraction methods could be observed, but the previously published extraction method was considered the best. UPLC columns with three different stationary phases (C8, C18, and phenyl) were used in identical experimental runs consisting of a total of 60 injections of extracted male and female plasma samples. The C8 column was determined to be the best for metabolic profiling analysis on plasma. The acquired UPLC/MS data of extracted male and female plasma samples was subjected to principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS–DA). Furthermore, a strategy for compound identification was applied here, demonstrating the strength of high-mass-accuracy time-of-flight (TOF)/MS analysis in metabolic profiling.

  • 13.
    Brännström, Thomas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Bergh, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Ekhtiari Bidhendi, Elaheh
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Marklund, Stefan M.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease2019Ingår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 29, s. 90-90Artikel i tidskrift (Övrigt vetenskapligt)
  • 14. Canosa, Antonio
    et al.
    De Marco, Giovanni
    Lomartire, Annarosa
    Rinaudo, Maria Teresa
    Di Cunto, Ferdinando
    Turco, Emilia
    Barberis, Marco
    Brunetti, Maura
    Casale, Federico
    Moglia, Cristina
    Calvo, Andrea
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Mora, Gabriele
    Chio, Adriano
    A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms2018Ingår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RTPCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate. 

  • 15. Danielsson, Jens
    et al.
    Awad, Wael
    Saraboji, Kadhirvel
    Kurnik, Martin
    Lang, Lisa
    Leinartaite, Lina
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Logan, Derek T
    Oliveberg, Mikael
    Global structural motions from the strain of a single hydrogen bond2013Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, nr 10, s. 3829-3834Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The origin and biological role of dynamic motions of folded enzymes is not yet fully understood. In this study, we examine the molecular determinants for the dynamic motions within the beta-barrel of superoxide dismutase 1 (SOD1), which previously were implicated in allosteric regulation of protein maturation and also pathological misfolding in the neurodegenerative disease amyotrophic lateral sclerosis. Relaxation-dispersion NMR, hydrogen/deuterium exchange, and crystallographic data show that the dynamic motions are induced by the buried H43 side chain, which connects the backbones of the Cu ligand H120 and T39 by a hydrogen-bond linkage through the hydrophobic core. The functional role of this highly conserved H120-H43-T39 linkage is to strain H120 into the correct geometry for Cu binding. Upon elimination of the strain by mutation H43F, the apo protein relaxes through hydrogen-bond swapping into a more stable structure and the dynamic motions freeze out completely. At the same time, the holo protein becomes energetically penalized because the twisting back of H120 into Cu-bound geometry leads to burial of an unmatched backbone carbonyl group. The question then is whether this coupling between metal binding and global structural motions in the SOD1 molecule is an adverse side effect of evolving viable Cu coordination or plays a key role in allosteric regulation of biological function, or both?

  • 16.
    Ekblom, Kim
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Stegmayr, Birgitta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Johansson, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Wiklund, Per-Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Iron stores and HFE genotypes are not related to increased risk of ischemic stroke.: a prospective nested case-referent study2007Ingår i: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 24, nr 5, s. 405-411Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: High iron levels can increase the formation of noxious oxygen radicals, which are thought to contribute to cerebrovascular disease. The aim of this prospective study was to determine if iron status and HFE genotypes constitute risk factors for stroke.

    Methods: First-ever stroke cases (231 ischemic and 42 hemorrhagic) and matched double referents from the population-based Northern Sweden cohorts were studied in a nested case-referent setting.

    Results: For total iron binding capacity, an increased risk of ischemic stroke was seen in the highest quartile (OR 1.80; 95% CI 1.14-2.83; p for trend 0.012). The highest quartile of transferrin iron saturation showed a decreased risk of ischemic stroke in men (OR 0.44; 95% CI 0.22-0.87; p for trend 0.028), but not in women. There was an increased risk of hemorrhagic stroke in the second (OR 4.07; 95% CI 1.09-15.20) and third quartile (OR 4.22; 95% CI 1.08-16.42) of ferritin. Neither quartiles of plasma iron concentrations nor the HFE C282Y and H63D genotypes were associated with ischemic or hemorrhagic stroke.

    Conclusions: Iron stores were not positively related to increased risk of ischemic stroke. Furthermore, HFE genotypes did not influence the risk of ischemic or hemorrhagic stroke. Copyright (c) 2007 S. Karger AG, Basel.

  • 17.
    Ekblom, Kim
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Iron stores and HFE genotypes are not related to increased risk of first-time myocardial infarction: a prospective nested case-referent study2011Ingår i: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 150, nr 2, s. 169-172Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Our objectives were to study the relationship between iron stores, HFE genotypes and the risk for first-ever myocardial infarction.

    Methods: First-ever myocardial infarction cases (n=618) and double matched referents from the Northern Sweden Health and Disease Cohort Study were studied in a prospective nested case-referent setting. Plasma iron, total iron binding capacity, transferrin iron saturation and ferritin were analyzed, as well as several confounders. HFE C282Y and H63D genotypes were determined.

    Results: There was an inverse risk association for myocardial infarction in the highest quartiles of iron (OR 0.68; 95% CI 0.48-0.96) and transferrin iron saturation (OR 0.62; 95% CI 0.42-0.89) in men. This association, however, was lost after adjusting for C-reactive protein. Women homozygous for H63D had a higher risk for myocardial infarction.

    Conclusions: No risk association between high iron stores and first-ever myocardial infarction was found. The higher risk in female H63D homozygotes is probably not related to iron metabolism.

  • 18.
    Ekblom, Kim
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Jansson, Jan-Håkan
    Medicinkliniken, Skellefteå lasarett.
    Osterman, Pia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting2010Ingår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, nr 3, s. 340-347Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Bilirubin, an effective antioxidant, shows a large variation in levels between individuals and has been positively associated with reduced cardiovascular disease risk. A major reason for the variability is a common promoter polymorphism, UGT1A1*28, which reduces the transcription of the enzyme that conjugates bilirubin, UDP-glucuronosyltransferase 1A1. The aim of the study was to evaluate a possible protective effect of plasma bilirubin and the UGT1A1*28 polymorphism against myocardial infarction in a prospective case-referent setting.

    Methods and Results: 618 subjects with a first-ever myocardial infarction (median event age 60.5 years, median lag time 3.5 years) and 1184 matched referents were studied. Plasma bilirubin was lower in cases vs. referents. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk of myocardial infarction. Among multiple other variables, serum iron showed one of the strongest associations with bilirubin levels.

    Conclusion: We found no evidence for a protective effect of the UGT1A1*28 polymorphism against myocardial infarction and consequently neither for bilirubin. The lower bilirubin levels in cases might be caused by decreased production, increased degradation or increased elimination.

  • 19.
    Ekblom, Kim
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Jansson, Jan-Håkan
    Osterman, Pia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Response to letter regarding article "Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective nested case-referent setting"2011Ingår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 4, nr 1, s. e2-Artikel i tidskrift (Refereegranskat)
  • 20.
    Ekblom, Kim
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, Lars
    Department of Medicine, Skellefteå County Hospital, Skellefteå, Sweden.
    Osterman, Pia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Wiklund, Per-Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting2010Ingår i: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 30, nr 6, s. 590-596Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase-1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke, have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting.

    Methods: Cases with first-ever ischemic stroke (n=231; median lag time 4.9 years), and 462 matched referents from the The Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis.

    Results: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%), showed a strong gene-dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analysed the strongest correlation with bilirubin was found for plasma iron.

    Conclusions: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke also might affect bilirubin levels.

  • 21.
    Ekblom, Kim
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Hultdin, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Iron Biomarkers in Plasma, HFE Genotypes, and the Risk for Colorectal Cancer in a Prospective Setting2012Ingår i: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 55, nr 3, s. 337-344Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: High iron levels can increase the formation of noxious oxygen radicals, which are thought to promote carcinogenesis. OBJECTIVE: The aim of this prospective study was to determine whether iron biomarkers and HFE genotypes, which influence iron regulation, constitute risk factors for colorectal cancer. DESIGN: This is a prospective nested case-referent study. SETTINGS: The study was performed within the population-based Northern Sweden Health and Disease Study. PATIENTS: The study included 226 cases of colorectal cancer and 437 matched referents. MAIN OUTCOME MEASURES: Conditional regression analysis was performed. Adjustments for smoking, smoking and BMI, and HFE C282Y and H63D were performed. RESULTS: The highest quintile of total iron-binding capacity showed significantly higher risk for colorectal cancer, unadjusted OR 2.35 (95% CI 1.38-4.02). When stratified by sex, the findings were only present in women (OR 3.34 (95% CI 1.59-7.02)). Ferritin was associated with reduced risk throughout quintiles 2 to 5 both in univariate and multivariate models. LIMITATIONS: Colorectal cancer may influence iron markers because of occult bleeding. Homozygotes for HFE C282Y were too few to make conclusions for this group. The relatively short follow-up time might be insufficient to detect risk of iron biomarkers. CONCLUSIONS: High iron levels do not increase the risk of colorectal cancer. HFE genotypes influencing iron uptake had no effect on colorectal cancer risk.

  • 22.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Bergh, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease2016Ingår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, nr 6, s. 2249-2253Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease.

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  • 23.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Pakkenberg, Bente
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis2018Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, nr 6, s. 939-953Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

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  • 24.
    Ezer, Shlomit
    et al.
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Daana, Muhannad
    Child Development Centers, Clalit Health Care Services, Israel.
    Park, Julien H.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Department of General Pediatrics, University of Münster, Münster, Germany.
    Yanovsky-Dagan, Shira
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel.
    Nordström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Basal, Adily
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel.
    Edvardson, Simon
    Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Pediatric Neurology Unit, Hadassah Medical Organization, Jerusalem, Israel.
    Saada, Ann
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Otto, Markus
    Department of Neurology, University Clinic, Ulm, Germany; Department of Neurology, University Clinic, Halle (Saale), Germany.
    Meiner, Vardiella
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter Munch
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Harel, Tamar
    Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
    Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity2022Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 145, nr 3, s. 872-878Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.

  • 25.
    Fahmy, Nagia
    et al.
    Neuromuscular Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Neuromuscular Research Unit, Neuropsychiatry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
    Müller, Kathrin
    Department of Neurology, Ulm University, Ulm, Germany; Institute of Human Genetics, Ulm University, Ulm University Medical Center, Ulm, Germany.
    Andersen, Peter Munch
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Otto, Markus
    Department of Neurology, Ulm University, Ulm, Germany.
    Ludolph, Albert C.
    Department of Neurology, Ulm University, Ulm, Germany; German Center for Neurodegenerative Diseases (DZNE), Ulm Site, Ulm, Germany.
    Hamdi, Nabila
    Molecular Pathology Unit, The German University in Cairo, Cairo, Egypt.
    A novel homozygous p.Ser69Pro SOD1 mutation causes severe young-onset ALS with decreased enzyme activity2023Ingår i: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 270, s. 1770-1773Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The dose–effect of various SOD1 mutations on SOD1 enzymatic activity offers valuable insights into ALS pathogenesis with possible therapeutic implications. Homozygous SOD1 mutations, yet scarce, are of special interest. We report a novel homozygous SOD1 mutation with decreased enzymatic activity and severe early onset ALS phenotype.

    Methods: Whole exome sequencing and targeted screening of commonly implicated genes were conducted. Repeat-primed PCR and fragment length analysis were used for C9orf72. Bi-directional Sanger sequencing was used for SOD1 and other genes. SOD1 activity was measured by direct spectrophotometry. Serum neurofilament light chain level was measured by the ELLA immunoassay system.

    Results: The homozygous patient for a novel SOD1 variant p.Ser69Pro showed poor SOD1 enzymatic activity (16% of controls) and an early onset ALS phenotype predominantly affecting lower motor neurons with rapid involvement of the trunk, upper limbs and bulbar muscles. The asymptomatic heterozygous relatives had at least 68% of normal enzyme activity. Level of serum neurofilament light chain was much higher (148 pg/ml) in the patient than the relatives who had normal levels (6–10 pg/ml).

    Conclusion: This novel mutation adds knowledge to the ALS genotype–phenotype spectrum and supports the strong dose–effect of SOD1 mutations associated with severely decreased enzymatic activity.

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  • 26.
    Forsberg, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis2011Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 121, nr 5, s. 623-634Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from 9 ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia and oligodendrocytes in ALS patients carrying and as well as lacking SOD1 mutations. There was negligible staining in neurodegenerative and non-neurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.

  • 27.
    Forsberg, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Graffmo, Karin S
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bergh, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    High expression of wild-type human superoxide dismutase-1 gives a model of sporadic ALSManuskript (preprint) (Övrigt vetenskapligt)
  • 28.
    Forsberg, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Graffmo, Karin Sixtensdotter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Pakkenberg, Bente
    Weber, Markus
    Nielsen, Martin
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter Munch
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes2019Ingår i: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, nr 8, s. 861-869Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.

    Methods: A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.

    Results: The 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1(WT) in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1(WT) inclusions. Minute amounts of misSOD1(WT) inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1(D90A) mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.

    Conclusions and relevance Abundant inclusions containing misfolded SOD1(WT) are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1(WT) can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

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  • 29.
    Forsberg, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Graffmo, Karin Sixtensdotter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Stenvall, Erica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Tabikh, Naima
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation2023Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 145, nr 1, s. 13-28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.

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  • 30.
    Forsberg, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jonsson, P Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Bergemalm, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Graffmo, Karin S
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jacobsson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Rosquist, Roland
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients2010Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 5, nr 7, s. e11552-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in CuZn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) and are found in 6% of ALS patients. Non-native and aggregation-prone forms of mutant SOD1s are thought to trigger the disease. Two sets of novel antibodies, raised in rabbits and chicken, against peptides spaced along the human SOD1 sequence, were by enzyme-linked immunosorbent assay and an immunocapture method shown to be specific for denatured SOD1. These were used to examine SOD1 in spinal cords of ALS patients lacking mutations in the enzyme. Small granular SOD1-immunoreactive inclusions were found in spinal motoneurons of all 37 sporadic and familial ALS patients studied, but only sparsely in 3 of 28 neurodegenerative and 2 of 19 non-neurological control patients. The granular inclusions were by confocal microscopy found to partly colocalize with markers for lysosomes but not with inclusions containing TAR DNA binding protein-43, ubiquitin or markers for endoplasmic reticulum, autophagosomes or mitochondria. Granular inclusions were also found in carriers of SOD1 mutations and in spinobulbar muscular atrophy (SBMA) patients and they were the major type of inclusion detected in ALS patients homozygous for the wild type-like D90A mutation. The findings suggest that SOD1 may be involved in ALS pathogenesis in patients lacking mutations in the enzyme.

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  • 31.
    Forsberg, Karin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Neurologkliniken NHHC-Västerbotten, Norrlands universitetssjukhus, Umeå.
    Tjust, Anton E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Norrlands universitetssjukhus, Umeå.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Norrlands universitetssjukhus, Umeå.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi. Norrlands universitetssjukhus, Umeå.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper. Neurologkliniken, NHHC-Västerbotten, Norrlands universitetssjukhus, Umeå.
    ALS kan vara en prionsjukdom: Inklusioner av felvecklat SOD1-protein tycks finnas hos patienter med alla typer av ALS2020Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 117, artikel-id FYT4Artikel i tidskrift (Refereegranskat)
  • 32.
    Forsgren, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lehmann, Manuela
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Weygandt Mathis, Mackenzie
    Keskin, Isil
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Nijssen, Jik
    Lowry, Emily
    Garcia, Alejandro
    Sandoe, Jackson
    Hedlund, Eva
    Wichterle, Hynek
    Henderson, Christopher
    Eggan, Kevin
    Kiskinis, Evangelos
    Andersen, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Gilthorpe, Jonathan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Enhanced protein misfolding in patient-derived models of amyotrophic lateral sclerosisManuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
  • 33.
    Forsgren, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nordin, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nordström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Rofougaran, Reza
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Danielsson, Jens
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Gilthorpe, Jonathan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersen, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    A Novel mutation D96Mfs*8 in SOD1 identified in a Swedish ALS patient results in a truncated and heavily aggregation-prone proteinManuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
  • 34.
    Graffmo, Karin S.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis2013Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, nr 1, s. 51-60Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A common cause of amyotrophic lateral sclerosis (ALS) is mutations in the gene encoding superoxide dismutase-1. There is evolving circumstantial evidence that the wild-type protein can also be neurotoxic and that it may more generally be involved in the pathogenesis of ALS. To test this proposition more directly, we generated mice that express wild-type human superoxide dismutase-1 at a rate close to that of mutant superoxide dismutase-1 in the commonly studied G93A transgenic model. These mice developed an ALS-like syndrome and became terminally ill after around 370 days. The loss of spinal ventral neurons was similar to that in the G93A and other mutant superoxide dismutase-1 models, and large amounts of aggregated superoxide dismutase-1 were found in spinal cords, but also in the brain. The findings show that wild-type human superoxide dismutase-1 has the ability to cause ALS in mice, and they support the hypothesis of a more general involvement of the protein in the disease in humans.

  • 35.
    Graffmo, Karin S
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    ALS patients with the SOD1 D90A mutation show both spinal cord and frontal cortical pathologyManuskript (preprint) (Övrigt vetenskapligt)
  • 36.
    Günther, René
    et al.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dresden, Germany.
    Pal, Arun
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Dresden High Magnetic Field Laboratory (HLD), Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
    Williams, Chloe
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Zimyanin, Vitaly L.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Department of Molecular Physiology and Biological Physics, University of Virginia, VA, Charlottesville, United States.
    Liehr, Maria
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    von Neubeck, Cläre
    German Cancer Consortium(DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay—National Center for Radiation Research in Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Clinic for Particle Therapy, West German Proton Therapy Centre Essen (WPE) gGmbH, University Medical Centre of Essen, Essen, Germany.
    Krause, Mechthild
    German Cancer Consortium(DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay—National Center for Radiation Research in Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden—Rossendorf, Institute of Radiooncology—OncoRay, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    Parab, Mrudula G.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    Petri, Susanne
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Kalmbach, Norman
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Sterneckert, Jared
    Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Wegner, Florian
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Gilthorpe, Jonathan D.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Hermann, Andreas
    Translational Neurodegeneration Section, Albrecht-Kossel, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany.
    Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS2022Ingår i: Cells, E-ISSN 2073-4409, Vol. 11, nr 7, artikel-id 1246Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.

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  • 37.
    Ingre, Caroline
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Press, R
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Erythrocyte SOD1 enzyme activity in ALS patients is not modulated by a 50 bp deletion in the alleged SOD1 promotorManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background A known cause of ALS are mutations in the SOD1 gene. There is also evidence that SOD1 may be involved in cases lacking mutations in the gene. A 50 bp deletion located 1684 bp upstream of the start codon of SOD1 has been suggested to reduce transcription of SOD1, affect enzymatic activity and to be associated with later disease onset in ALS patients. The findings have been challenged by a study of Italian ALS patients, and here we examined the 50 bp deletion in Swedish ALS patients and controls. 

    Methods Blood samples from 543 Swedish ALS patients and 356 Swedish controls were analysed for the 50 bp deletion and for SOD1 enzymic activity. The results were related to the disease phenotype of the patients.

    Results The frequency of the 50 bp deletion was the same in the patient and control cohorts, and both were found to be in Hardy-Weinberg equilibrium regarding the deletion. In relation to the different genotypes, no differences were detected in SOD1 enzymic activity, duration of disease, age of onset or site of onset.

    Conclusions When interpreting the present results together with previous results from other populations, we find it unlikely that the 50 bp deletion region has any regulatory function for the SOD1 gene, nor any effects on the phenotype of ALS.

  • 38.
    Ingre, Caroline
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Wuolikainen, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Press, Rayomand
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    A 50bp deletion in the SOD1 promoter lowers enzyme expression but is not associated with ALS in Sweden2016Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 17, nr 5-6, s. 452-457Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in the superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). A 50 base pair (bp) deletion of SOD1 has been suggested to reduce transcription and to be associated with later disease onset in ALS. This study was aimed to reveal if the 50bp deletion influenced SOD1 enzymatic activity, occurrence and phenotype of the disease in a Swedish ALS/control cohort. Blood samples from 512 Swedish ALS patients and 354 Swedish controls without coding SOD1 mutations were analysed for the 50bp deletion allele. The enzymatic activity of SOD1 in erythrocytes was analysed and genotype-phenotype correlations were assessed. Results demonstrated that the genotype frequencies of the 50bp deletion were all found to be in Hardy-Weinberg equilibrium. No significant differences were found for age of onset, disease duration or site of onset. SOD1 enzymatic activity showed a statistically significant decreasing trend in the control group, in which the allele was associated with a 5% reduction in SOD1 activity. The results suggest that the 50bp deletion has a moderate reducing effect on SOD1 synthesis. No modulating effects, however, were found on ALS onset, phenotype and survival in the Swedish population.

  • 39.
    Jiye, A
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Granström, Micael
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Marklund, Stefan
    Johansson, Annika
    Stenlund, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Moritz, Thomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jiye, A
    Guangji, Wang
    Dynamic modification of blood erythrocytes metabolism based on GC/TOF-MS analysis2006Övrigt (Övrig (populärvetenskap, debatt, mm))
  • 40. Jiye, A
    et al.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gullberg, Jonas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Moritz, Thomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Marklund, Stefan
    Global analysis of low-molecular-weight compounds in human plasma using GC/TOF-MS2004Ingår i: DRUG METABOLISM REVIEWS, ISSN 0360-2532, Vol. 36, s. 246-246Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    We developed a method for analysis of low-molecular-weight compounds (LMWC) in human plasma involving extraction of metabolites by organic solvents, derivatization of extract and final analysis by GC/TOF-MS. The overall strategy for the development of the method was based on using design-of-experimental (DOE), and data evaluation based on multivariate statistical tools like PCA and PLS. The results showed that the extraction efficiency for different solvents varied, and that methanol was important for high reproducibility. More than 300 compounds could be detected in one analysis. Forty five of them were identified, including amino acids, lipids and free fatty acids, organic acids, carbohydrates and so on. The quantitative data of these metabolites showed, with two exceptions, high precision and good linearity between response and concentration. By using this method it is now possible to analyze plasma samples with high throughput to identify metabolic biomarkers for different kinds of diseases.

  • 41. Johansson, Ann-Sofi
    et al.
    Vestling, Monika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Zetterström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lang, Lisa
    Leinartaite, Lina
    Karlstrom, Mikael
    Danielsson, Jens
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Oliveberg, Mikael
    Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation2012Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 7, nr 4, s. e36104-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neurodegeneration in protein-misfolding disease is generally assigned to toxic function of small, soluble protein aggregates. Largely, these assignments are based on observations of cultured neural cells where the suspect protein material is titrated directly into the growth medium. In the present study, we use this approach to shed light on the cytotoxic action of the metalloenzyme Cu/Zn superoxide dismutase 1 (SOD1), associated with misfolding and aggregation in amyotrophic lateral sclerosis (ALS). The results show, somewhat unexpectedly, that the toxic species of SOD1 in this type of experimental setting is not an aggregate, as typically observed for proteins implicated in other neuro-degenerative diseases, but the folded and fully soluble apo protein. Moreover, we demonstrate that the toxic action of apoSOD1 relies on the protein's ability to chelate Zn2+ ions from the growth medium. The decreased cell viability that accompanies this extraction is presumably based on disturbed Zn2+ homeostasis. Consistently, mutations that cause global unfolding of the apoSOD1 molecule or otherwise reduce its Zn2+ affinity abolish completely the cytotoxic response. So does the addition of surplus Zn2+. Taken together, these observations point at a case where the toxic response of cultured cells might not be related to human pathology but stems from the intrinsic limitations of a simplified cell model. There are several ways proteins can kill cultured neural cells but all of these need not to be relevant for neurodegenerative disease.

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  • 42.
    Jonsson, P Andreas
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Bergemalm, Daniel
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Andersen, Peter M
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurologi. Neurologi.
    Gredal, Ole
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Marklund, Stefan L
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Inclusions of amyotrophic lateral sclerosis-linked superoxide dismutase in ventral horns, liver, and kidney2008Ingår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 63, nr 5, s. 671-675Artikel i tidskrift (Refereegranskat)
  • 43.
    Jonsson, P Andreas
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Graffmo, Karin
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurologi.
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Lindberg, Mikael
    Oliveberg, Mikael
    Marklund, Stefan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models.2006Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 129, nr Pt 2, s. 451-644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.

  • 44.
    Jonsson, P Andreas
    et al.
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Graffmo, Karin
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi. Patologi.
    Nilsson, Peter
    Andersen, Peter M
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurologi. Neurologi.
    Marklund, Stefan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi. Klinisk kemi.
    Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1.2006Ingår i: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 65, nr 12, s. 1126-1136Artikel i tidskrift (Refereegranskat)
  • 45.
    Jonsson, P Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Graffmo, Karin S
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Superoxide dismutase in amyotrophic lateral sclerosis patients homozygous for the D90A mutation2009Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 36, nr 3, s. 421-424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The most common of the amyotrophic lateral sclerosis (ALS)-associated superoxide dismutase-1 (SOD1) mutations, D90A, differs from others in its high structural stability and by the existence of both recessive and dominant inheritance. Here SOD1 in CNS and peripheral organs from five ALS patients homozygous for D90A were compared to controls. In most areas, including ventral horns, there were no significant differences in SOD1 activities and Western blotting patterns between controls and D90A cases. The SOD1 activities in areas vulnerable to mutant SOD1s, ventral horns and precentral gyrus were intermediate among CNS areas and much lower than in kidney and liver. Thus, the vulnerability of motor areas is not explained by high SOD1 content. The findings argue against the idea of expression-reducing protective factors being present near the D90A locus in recessive pedigrees. The similarity to wild-type SOD1 prompts speculations on the involvement of the latter in sporadic ALS.

  • 46. Jung, Oliver
    et al.
    Marklund, Stefan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Xia, Ning
    Busse, Rudi
    Brandes, Ralf P
    Inactivation of extracellular superoxide dismutase contributes to the development of high-volume hypertension.2007Ingår i: Arterioscler Thromb Vasc Biol, ISSN 1524-4636, Vol. 27, nr 3, s. 470-7Artikel i tidskrift (Refereegranskat)
  • 47. Juul, Klaus
    et al.
    Tybjaerg-Hansen, Anne
    Marklund, Stefan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Heegaard, Niels H H
    Steffensen, Rolf
    Sillesen, Henrik H
    Jensen, Gorm B
    Nordestgaard, BG
    [Genetically determined reduction in antioxidative protection and increased risk of ischemic heart disease--secondary publication]2005Ingår i: Ugeskr Laeger, ISSN 0041-5782, Vol. 167, nr 7, s. 767-70Artikel i tidskrift (Övrigt vetenskapligt)
  • 48. Juul, Klaus
    et al.
    Tybjaerg-Hansen, Anne
    Marklund, Stefan
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Heegaard, Niels H H
    Steffensen, Rolf
    Sillesen, Henrik
    Jensen, Gorm
    Nordestgaard, Börge G
    Genetically reduced antioxidative protection and increased ischemic heart disease risk: The Copenhagen City Heart Study.2004Ingår i: Circulation, ISSN 1524-4539, Vol. 109, nr 1, s. 59-65Artikel i tidskrift (Refereegranskat)
  • 49. Katz, Jonathan S.
    et al.
    Katzberg, Hans D.
    Woolley, Susan C.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Combined fulminant frontotemporal dementia and amyotrophic lateral sclerosis associated with an I113T SOD1 mutation2012Ingår i: AMYOTROPH LATERAL SC, ISSN 1748-2968, Vol. 13, nr 6, s. 567-569Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in the gene for superoxide dismutase type 1 cause amyotrophic lateral sclerosis (ALS), but are not thought to be associated with frontotemporal dementia (FTD). A lack of detailed case reports is one reason, among others, for this skepticism. This case report comments on a patient with familial ALS caused by I113T mutation in the SOD1 gene presenting with progressive cognitive and behavioral decline two years before developing progressive motor degeneration. In conclusion, this case provides evidence that SOD1 mutations can be associated with FTD.

  • 50.
    Keskin, Isil
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Birve, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Berdynski, Mariusz
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Polish Academy of Sciences, Warsaw, Poland.
    Hjertkvist, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Rofougaran, Reza
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Glass, Jonathan D.
    Marklund, Stefan L.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives2017Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, nr 5-6, s. 457-463Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations.Methods: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay.Results: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72(HRE). In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios.Conclusion: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.

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