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  • 1.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hempel, Maja
    Santer, René
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Tsiakas, Konstantinos
    Johannsen, Jessika
    Volk, Alexander E.
    Bierhals, Tatjana
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Phenotype in an Infant with SOD1 Homozygous Truncating Mutation2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 5, p. 486-488Article in journal (Refereed)
  • 2.
    Bergh, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Graffmo, Karin Sixtensdotter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Jonsson, P. Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lang, Lisa
    Stockholm, Sweden.
    Danielsson, Jens
    Stockholm, Sweden.
    Oliveberg, Mikael
    Stockholm, Sweden.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 14, p. 4489-4494Article in journal (Refereed)
    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.

  • 3.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease2016In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 6, p. 2249-2253Article in journal (Refereed)
    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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  • 4.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pakkenberg, Bente
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis2018In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 6, p. 939-953Article in journal (Refereed)
    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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  • 5.
    Ekhtiari Bidhendi, Elaheh
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, SL
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Superoxide dismutase prions transmit fatal ALS to transgenic mice which do not spontaneously develop symptomsManuscript (preprint) (Other academic)
  • 6.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High expression of wild-type human superoxide dismutase-1 gives a model of sporadic ALSManuscript (preprint) (Other academic)
  • 7.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Neurologkliniken NHHC-Västerbotten, Norrlands universitetssjukhus, Umeå.
    Tjust, Anton E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Norrlands universitetssjukhus, Umeå.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Norrlands universitetssjukhus, Umeå.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Norrlands universitetssjukhus, Umeå.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Neurologkliniken, NHHC-Västerbotten, Norrlands universitetssjukhus, Umeå.
    ALS kan vara en prionsjukdom: Inklusioner av felvecklat SOD1-protein tycks finnas hos patienter med alla typer av ALS2020In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 117, article id FYT4Article in journal (Refereed)
  • 8.
    Forsgren, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lehmann, Manuela
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weygandt Mathis, Mackenzie
    Keskin, Isil
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nijssen, Jik
    Lowry, Emily
    Garcia, Alejandro
    Sandoe, Jackson
    Hedlund, Eva
    Wichterle, Hynek
    Henderson, Christopher
    Eggan, Kevin
    Kiskinis, Evangelos
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Enhanced protein misfolding in patient-derived models of amyotrophic lateral sclerosisManuscript (preprint) (Other (popular science, discussion, etc.))
  • 9.
    Graffmo, Karin S.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis2013In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 1, p. 51-60Article in journal (Refereed)
    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.

  • 10. Johansson, Ann-Sofi
    et al.
    Vestling, Monika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lang, Lisa
    Leinartaite, Lina
    Karlstrom, Mikael
    Danielsson, Jens
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Oliveberg, Mikael
    Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 4, p. e36104-Article in journal (Refereed)
    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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  • 11.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Elin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lange, Dale J.
    Synofzik, Matthis
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Low oxygen tension induces misfolding and aggregation of superoxide dismutase in ALS patient-derived motor neuronsManuscript (preprint) (Other academic)
  • 12.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsgren, Elin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lehmann, Manuela
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lange, Dale J.
    Synofzik, Matthis
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension2019In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 85-101Article in journal (Refereed)
    Abstract [en]

    Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O2 is required for formation of the bond, we reasoned that low O2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low oxygen tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.

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  • 13. Lang, Lisa
    et al.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Danielsson, Jens
    Oliveberg, Mikael
    SOD1 aggregation in ALS mice shows simplistic test tube behavior2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 32, p. 9878-9883Article in journal (Refereed)
    Abstract [en]

    A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.

  • 14.
    Lehmann, Manuela
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Marklund, Matthew
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bolender, Anna-Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Bidhendi, Elaheh E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice2020In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 8, no 1, article id 161Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.

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  • 15.
    Nordlund, Anna
    et al.
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Leinartaitė, Lina
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Saraboji, Kadhirvel
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Aisenbrey, Christopher
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Danielsson, Jens
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Logan, Derek T
    Department of Molecular Biophysics, Lund University, S-221 00 Lund, Sweden.
    Oliveberg, Mikael
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Functional features cause misfolding of the ALS-provoking enzyme SOD12009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 24, p. 9667-9672Article in journal (Refereed)
    Abstract [en]

    The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn2+ loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a nonnative Zn2+ ion with μM affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site, however, the Cu ligands fail to correctly coordinate the nonnative Zn2+ ion: Trapping of a water molecule causes H48 to change rotamer and swing outwards. The misligation is sterically incompatible with the native structure. As a consequence, SOD1 unfolds locally and interacts with neighboring molecules in the crystal lattice. The findings point to a critical role for the native Zn site in controlling SOD1 misfolding, and show that even subtle changes of the metal-loading sequence can render the wild-type protein the same structural properties as ALS-provoking mutations. This frustrated character of the SOD1 molecule seems to arise from a compromise between optimization of functional and structural features.

  • 16.
    Nordström, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Lang, Lisa
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, Stockholm, Sweden.
    Ekhtiari Bidhendi, Elaheh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Oliveberg, Mikael
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, Stockholm, Sweden.
    Danielsson, Jens
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, Stockholm, Sweden.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Mutant SOD1 aggregates formed in vitro and in cultured cells are polymorphic and differ from those arising in the CNS2023In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 164, no 1, p. 77-93Article in journal (Refereed)
    Abstract [en]

    Mutations in the human Superoxide dismutase 1 (hSOD1) gene are well-established cause of the motor neuron disease ALS. Patients and transgenic (Tg) ALS model mice carrying mutant variants develop hSOD1 aggregates in the CNS. We have identified two hSOD1 aggregate strains, which both transmit spreading template-directed aggregation and premature fatal paralysis when inoculated into adult transgenic mice. This prion-like spread of aggregation could be a primary disease mechanism in SOD1-induced ALS. Human SOD1 aggregation has been studied extensively both in cultured cells and under various conditions in vitro. To determine how the structure of aggregates formed in these model systems related to disease-associated aggregates in the CNS, we used a binary epitope-mapping assay to examine aggregates of hSOD1 variants G93A, G85R, A4V, D90A, and G127X formed in vitro, in four different cell lines and in the CNS of Tg mice. We found considerable variability between replicate sets of in vitro-generated aggregates. In contrast, there was a high similarity between replicates of a given hSOD1 mutant in a given cell line, but pronounced variations between different hSOD1 mutants and different cell lines in both structures and amounts of aggregates formed. The aggregates formed in vitro or in cultured cells did not replicate the aggregate strains that arise in the CNS. Our findings suggest that the distinct aggregate morphologies in the CNS could result from a micro-environment with stringent quality control combined with second-order selection by spreading ability. Explorations of pathogenesis and development of therapeutics should be conducted in models that replicate aggregate structures forming in the CNS. (Figure presented.)

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  • 17.
    Park, Julien H.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Department of General Paediatrics, University of Münster, Münster, Germany.
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Tsiakas, Konstantinos
    Department of Paediatrics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
    Keskin, Isil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elpers, Christiane
    Department of General Paediatrics, University of Münster, Münster, Germany.
    Mannil, Manoj
    Clinic for Radiology, University Hospital Münster, WWU University of Münster, Münster, Germany.
    Heller, Raoul
    Starship Children's Health, Auckland City Hospital, Auckland, New Zealand.
    Nolan, Melinda
    Starship Children's Health, Auckland City Hospital, Auckland, New Zealand.
    Alburaiky, Salam
    Starship Children's Health, Auckland City Hospital, Auckland, New Zealand.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hempel, Maja
    Department of Paediatrics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    Schara-Schmidt, Ulrike
    Department of Paediatric Neurology, University Hospital Essen, Essen, Germany.
    Biskup, Saskia
    CeGAT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany.
    Steinacker, Petra
    Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
    Otto, Markus
    Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
    Weishaupt, Jochen
    Division for Neurodegenerative Diseases, Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
    Hahn, Andreas
    Department of Child Neurology, Justus Liebig University, Giessen, Germany.
    Santer, Rene
    Department of Paediatrics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
    Marquardt, Thorsten
    Department of General Paediatrics, University of Münster, Münster, Germany.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-12023In: Brain Communications, E-ISSN 2632-1297, Vol. 5, no 1, article id fcad017Article in journal (Refereed)
    Abstract [en]

    Superoxide dismutase-1 is a ubiquitously expressed antioxidant enzyme. Mutations in SOD1 can cause amyotrophic lateral sclerosis, probably via a toxic gain-of-function involving protein aggregation and prion-like mechanisms. Recently, homozygosity for loss-of-function mutations in SOD1 has been reported in patients presenting with infantile-onset motor neuron disease. We explored the bodily effects of superoxide dismutase-1 enzymatic deficiency in eight children homozygous for the p.C112Wfs∗11 truncating mutation. In addition to physical and imaging examinations, we collected blood, urine and skin fibroblast samples. We used a comprehensive panel of clinically established analyses to assess organ function and analysed oxidative stress markers, antioxidant compounds, and the characteristics of the mutant Superoxide dismutase-1. From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage. The disease progression seemed to slow down over the following years. The p.C112Wfs∗11 gene product is unstable, rapidly degraded and no aggregates were found in fibroblast. Most laboratory tests indicated normal organ integrity and only a few modest deviations were found. The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione. A variety of other antioxidants and oxidant damage markers were within normal range. In conclusion, non-neuronal organs in humans show a remarkable tolerance to absence of Superoxide dismutase-1 enzymatic activity. The study highlights the enigmatic specific vulnerability of the motor system to both gain-of-function mutations in SOD1 and loss of the enzyme as in the here depicted infantile superoxide dismutase-1 deficiency syndrome.

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  • 18.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a disease in which the motor neurons die in a progressive manner, leading to paralysis and muscle wasting. ALS is always fatal, usually through respiratory failure when the disease reaches muscles needed for breathing. Most cases are sporadic, but approximately 5–10% are familial. The first gene to be linked to familial ALS encodes the antioxidant enzyme superoxide dismutase-1 (SOD1). Today, more than 160 different mutations in SOD1 have been found in ALS patients.  The mutant SOD1 proteins cause ALS by gain of a toxic property that should be common to all. Aggregates of SOD1 in motor neurons are hallmarks of ALS patients and transgenic models carrying mutant SOD1s, suggesting that misfolding, oligomerization, and aggregation of the protein may be involved in the pathogenesis. SOD1 is normally a very stable enzyme, but the structure has several components that make SOD1 sensitive to misfolding. The aim of the work in this thesis was to study misfolded SOD1 in vivo.

    Small amounts of soluble misfolded SOD1 were identified as a common denominator in transgenic ALS models expressing widely different forms of mutant SOD1, as well as wild-type SOD1. The highest levels of misfolded SOD1 were found in the vulnerable spinal cord. The amounts of misfolded SOD1 were similar in all the different models and showed a broad correlation with the lifespan of the different mouse strains. The misfolded SOD1 lacked the C57-C146 intrasubunit disulfide bond and the stabilizing zinc and copper ions, and was prinsipally monomeric. Forms with higher apparent molecular weights were also found, some of which might be oligomers. Misfolding-prone monomeric SOD1 appeared to be the principal source of misfolded SOD1 in the CNS. Misfolded SOD1 in the spinal cord was found to interact mainly with chaperones, with Hsc70 being the most important. Only a minor proportion of the Hsc70 was sequestered by SOD1, however, suggesting that chaperone depletion is not involved in ALS.

     SOD1 is normally found in the cytoplasm but can be secreted. Extracellular mutant SOD1 has been found to be toxic to motor neurons and glial cells. Misfolded SOD1 in the extracellular space could be involved in the spread of the disease between different areas of the CNS and activate glial cells known to be important in ALS. The best way to study the interstitium of the CNS is through the cerebrospinal fluid (CSF), 30% of which is derived from the interstitial fluid. Antibodies specific for misfolded SOD1 were used to probe CSF from ALS patients and controls for misfolded SOD1. We did find misfolded SOD1 in CSF, but at very low levels, and there was no difference between ALS patients and controls. This argues against there being a direct toxic effect of extracellular SOD1 in ALS pathogenesis.

    In conclusion, soluble misfolded SOD1 is a common denominator for transgenic ALS model mice expressing widely different mutant SOD1 proteins. The misfolded SOD1 is mainly monomeric, but also bound to chaperones, and possibly exists in oligomeric forms also. Misfolded SOD1 in the interstitium might promote spread of aggregation and activate glial cells, but it is too scarce to directly cause cytotoxicity.

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  • 19.
    Zetterström, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Misfolded superoxide dismutase-1 in CSF from amyotrophic lateral sclerosis patients2011In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 117, no 1, p. 91-99Article in journal (Refereed)
    Abstract [en]

    Several of the superoxide dismutase-1 (SOD1) mutations linked to amyotrophic lateral sclerosis (ALS) lead to synthesis of structurally defective molecules, suggesting that any cytotoxic conformational species common for all mutations should be misfolded. SOD1 can be secreted and evidence from ALS model systems suggests that extracellular SOD1 may be involved in cytotoxicity. Three ELISAs specifically reacting with different sequence segments in misfolded SOD1 species were used for analysis of CSF from 38 neurological controls and from 96 ALS patients, 57 of whom were sporadic cases and 39 familial, including 22 patients carrying SOD1 mutations. Misfolded SOD1 was found in all samples. There were, however, no significant differences between patients with and without mutations, and between all the ALS patients and the controls. The estimated concentration of misfolded SOD1 in the interstitium of the CNS is a 1000 times lower than that required for appreciable cytotoxicity in model systems. The results argue against a direct cytotoxic role of extracellular misfolded SOD1 in ALS. Misfolded SOD1 in CSF cannot be used as a biomarker of ALS in patients with and without mutations in the enzyme.

  • 20.
    Zetterström, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Composition of soluble misfolded superoxide Dismutase-1 in murine models of Amyotrophic Lateral Sclerosis2013In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 15, no 1, p. 147-158Article in journal (Refereed)
    Abstract [en]

    A common cause of amyotrophic lateral sclerosis is mutations in superoxide dismutase-1, which provoke the disease by an unknown mechanism. We have previously found that soluble hydrophobic misfolded mutant human superoxide dismutase-1 species are enriched in the vulnerable spinal cords of transgenic model mice. The levels were broadly inversely correlated with life spans, suggesting involvement in the pathogenesis. Here, we used methods based on antihuman superoxide dismutase-1 peptide antibodies specific for misfolded species to explore the composition and amounts of soluble misfolded human superoxide dismutase-1 in tissue extracts. Mice expressing 5 different human superoxide dismutase-1 variants with widely variable structural characteristics were examined. The levels were generally higher in spinal cords than in other tissues. The major portion of misfolded superoxide dismutase-1 was shown to be monomers lacking the C57-C146 disulfide bond with large hydrodynamic volume, indicating a severely disordered structure. The remainder of the misfolded protein appeared to be non-covalently associated in 130- and 250-kDa complexes. The malleable monomers should be prone to aggregate and associate with other cellular components, and should be easily translocated between compartments. They may be the primary cause of toxicity in superoxide dismutase-1-induced amyotrophic lateral sclerosis.

  • 21.
    Zetterström, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Proteins that bind to misfolded mutant superoxide dismutase-1 in spinal cords from transgenic ALS model mice2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 23, p. 20130-20136Article in journal (Refereed)
    Abstract [en]

    Mutant superoxide dismutase-1 (SOD1) has an unidentified toxic property that provokes ALS. Several ALS-linked SOD1 mutations cause long C-terminal truncations, which suggests that common cytotoxic SOD1 conformational species should be misfolded and that the C-terminal end cannot be involved. The cytotoxicity may arise from interaction of cellular proteins with misfolded SOD1 species. Here we specifically immunocaptured misfolded SOD1 by the C-terminal end, from extracts of spinal cords from transgenic ALS model mice. Associated proteins were identified with proteomic techniques. Two transgenic models expressing SOD1s with contrasting molecular properties were examined: the stable G93A mutant, which is abundant in the spinal cord with only a tiny subfraction misfolded, and the scarce disordered truncation mutant G127insTGGG. For comparison, proteins in spinal cord extracts with affinity for immobilized apo G93A mutant SOD1 were determined. Two-dimensional gel patterns with a limited number of bound proteins were found, which were similar for the two SOD1 mutants. Apart from neurofilament light, the proteins identified were all chaperones and by far most abundant was Hsc70. The immobilized apo G93A SOD1, which would populate a variety of conformations, was found to bind to a considerable number of additional proteins. A substantial proportion of the misfolded SOD1 in the spinal cord extracts appeared to be chaperone-associated. Still, only about 1% of the Hsc70 appeared to be associated with misfolded SOD1. The results argue against the notion that chaperone depletion is involved in ALS pathogenesis in the transgenic models and in humans carrying SOD1 mutations.

  • 22.
    Zetterström, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Structure of soluble misfolded superoxide dismutase-1 in murine ALS modelsManuscript (preprint) (Other academic)
  • 23.
    Zetterström, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Stewart, Heather G
    Bergemalm, Daniel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jonsson, P Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oliveberg, Mikael
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 35, p. 14157-14162Article in journal (Refereed)
    Abstract [en]

    Mutants of superoxide dismutase-1 (SOD1) cause ALS by an unidentified cytotoxic mechanism. We have previously shown that the stable SOD1 mutants D90A and G93A are abundant and show the highest levels in liver and kidney in transgenic murine ALS models, whereas the unstable G85R and G127X mutants are scarce but enriched in the CNS. These data indicated that minute amounts of misfolded SOD1 enriched in the motor areas might exert the ALS-causing cytotoxicity. A hydrophobic interaction chromatography (HIC) protocol was developed with the aim to determine the abundance of soluble misfolded SOD1 in tissues in vivo. Most G85R and G127X mutant SOD1s bound in the assay, but only minute subfractions of the D90A and G93A mutants. The absolute levels of HIC-binding SOD1 were, however, similar and broadly inversely related to lifespans in the models. They were generally enriched in the susceptible spinal cord. The HIC-binding SOD1 was composed of disulfide-reduced subunits lacking metal ions and also subunits that apparently carried nonnative intrasubunit disulfide bonds. The levels were high from birth until death and were comparable to the amounts of SOD1 that become sequestered in aggregates in the terminal stage. The HIC-binding SOD1 species ranged from monomeric to trimeric in size. These species form a least common denominator amongst SOD1 mutants with widely different molecular characteristics and might be involved in the cytotoxicity that causes ALS.

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