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Zetterström, Per
Publications (10 of 19) Show all publications
Andersen, P. M., Hempel, M., Santer, R., Nordström, U., Tsiakas, K., Johannsen, J., . . . Marklund, S. L. (2019). Phenotype in an Infant with SOD1 Homozygous Truncating Mutation [Letter to the editor]. New England Journal of Medicine, 381(5), 486-488
Open this publication in new window or tab >>Phenotype in an Infant with SOD1 Homozygous Truncating Mutation
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2019 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 5, p. 486-488Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Massachusetts Medical Society, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-162395 (URN)10.1056/NEJMc1905039 (DOI)000478064200016 ()31314961 (PubMedID)
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Keskin, I., Forsgren, E., Lehmann, M., Andersen, P. M., Brännström, T., Lange, D. J., . . . Gilthorpe, J. D. (2019). The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension. Acta Neuropathologica, 138(1), 85-101
Open this publication in new window or tab >>The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension
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2019 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 85-101Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
New York: Springer, 2019
Keywords
Amyotrophic lateral sclerosis (ALS), Superoxide dismutase 1 (SOD1), Disulfide bond, Oxygen tension, Protein disorder, Protein aggregation, Patient-derived cells
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-157037 (URN)10.1007/s00401-019-01986-1 (DOI)000471708700005 ()30863976 (PubMedID)
Funder
Swedish Research Council, VRMH 2015-02804Knut and Alice Wallenberg Foundation, 2012.0091Västerbotten County CouncilThe Kempe FoundationsThe Swedish Brain Foundation, Hjarnfonden FO2015-0234
Note

Originally included in thesis in manuscript form.

Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-07-12Bibliographically approved
Ekhtiari Bidhendi, E., Bergh, J., Zetterström, P., Forsberg, K., Pakkenberg, B., Andersen, P. M., . . . Brännström, T. (2018). Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis. Acta Neuropathologica, 136(6), 939-953
Open this publication in new window or tab >>Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis
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2018 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 6, p. 939-953Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Superoxide dismutase, prion-like, aggregation, propagation, motor neuron disease
National Category
Neurosciences
Research subject
Neurology; Pathology
Identifiers
urn:nbn:se:umu:diva-150909 (URN)10.1007/s00401-018-1915-y (DOI)000451952700008 ()30284034 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseThe Swedish Brain FoundationThe Kempe FoundationsVästerbotten County Council
Note

Originally included in thesis in manuscript form.

Available from: 2018-08-18 Created: 2018-08-18 Last updated: 2019-09-12Bibliographically approved
Ekhtiari Bidhendi, E., Bergh, J., Zetterström, P., Andersen, P. M., Marklund, S. L. & Brännström, T. (2016). Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease. Journal of Clinical Investigation, 126(6), 2249-2253
Open this publication in new window or tab >>Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease
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2016 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 6, p. 2249-2253Article in journal (Refereed) Published
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.

National Category
Medical Bioscience Neurosciences
Identifiers
urn:nbn:se:umu:diva-122554 (URN)10.1172/JCI84360 (DOI)000377027500021 ()27140399 (PubMedID)
Available from: 2016-07-25 Created: 2016-06-20 Last updated: 2019-09-12Bibliographically approved
Lang, L., Zetterström, P., Brännström, T., Marklund, S. L., Danielsson, J. & Oliveberg, M. (2015). SOD1 aggregation in ALS mice shows simplistic test tube behavior. Proceedings of the National Academy of Sciences of the United States of America, 112(32), 9878-9883
Open this publication in new window or tab >>SOD1 aggregation in ALS mice shows simplistic test tube behavior
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2015 (English)In: 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) Published
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.

Keywords
superoxide dismutase 1, aggregation, transgenic mice, aggregation kinetics
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-108139 (URN)10.1073/pnas.1503328112 (DOI)000359285100046 ()26221023 (PubMedID)
Available from: 2015-09-18 Created: 2015-09-04 Last updated: 2018-06-07Bibliographically approved
Bergh, J., Zetterström, P., Andersen, P. M., Brännström, T., Graffmo, K. S., Jonsson, P. A., . . . Marklund, S. (2015). Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping. Proceedings of the National Academy of Sciences of the United States of America, 112(14), 4489-4494
Open this publication in new window or tab >>Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping
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2015 (English)In: 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) Published
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.

Place, publisher, year, edition, pages
National Academy of Sciences, 2015
Keywords
protein aggregation, neurodegeneration, strain, amyotrophic lateral sclerosis, transgenic mice
National Category
Pharmacology and Toxicology Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-103147 (URN)10.1073/pnas.1419228112 (DOI)000352287800075 ()25802384 (PubMedID)
Available from: 2015-05-28 Created: 2015-05-18 Last updated: 2018-08-19Bibliographically approved
Zetterström, P., Graffmo, K. S., Andersen, P. M., Brännström, T. & Marklund, S. L. (2013). Composition of soluble misfolded superoxide Dismutase-1 in murine models of Amyotrophic Lateral Sclerosis. Neuromolecular medicine, 15(1), 147-158
Open this publication in new window or tab >>Composition of soluble misfolded superoxide Dismutase-1 in murine models of Amyotrophic Lateral Sclerosis
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2013 (English)In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 15, no 1, p. 147-158Article in journal (Refereed) Published
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.

Keywords
Amyotropic lateral sclerosis, Superoxide dismutase (SOD), Protein misfolding, Transgenic mice, Neurodegeneration, Disulfide reduction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-67801 (URN)10.1007/s12017-012-8204-z (DOI)000315631000012 ()
Available from: 2013-04-05 Created: 2013-04-03 Last updated: 2018-06-08Bibliographically approved
Graffmo, K. S., Forsberg, K., Bergh, J., Birve, A., Zetterström, P., Andersen, P. M., . . . Brännström, T. (2013). Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Human Molecular Genetics, 22(1), 51-60
Open this publication in new window or tab >>Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis
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2013 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 1, p. 51-60Article in journal (Refereed) Published
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.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-63578 (URN)10.1093/hmg/dds399 (DOI)000312643400004 ()23026746 (PubMedID)
Available from: 2013-01-03 Created: 2013-01-03 Last updated: 2018-08-19Bibliographically approved
Johansson, A.-S., Vestling, M., Zetterström, P., Lang, L., Leinartaite, L., Karlstrom, M., . . . Oliveberg, M. (2012). Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation. PLoS ONE, 7(4), e36104
Open this publication in new window or tab >>Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e36104-Article in journal (Refereed) Published
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.

National Category
Microbiology in the medical area Neurosciences
Identifiers
urn:nbn:se:umu:diva-57388 (URN)10.1371/journal.pone.0036104 (DOI)000305345200116 ()
Available from: 2012-07-17 Created: 2012-07-16 Last updated: 2018-06-08Bibliographically approved
Zetterström, P. (2011). Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Felveckat superoxiddismutas-1 i amyotrofisk lateralskelros
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.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2011. p. 126
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1421
Keywords
ALS, SOD1, protein misfolding, SOD1 conformation, disulfide-reduced, transgenic mice, cerebrospinal fluid, protein-protein interaction, antibodies
National Category
Other Clinical Medicine
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:umu:diva-43898 (URN)978-91-7459-215-3 (ISBN)
Public defence
2011-09-09, Hörsal Betula, Building 6M, Umeå University, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-05-20 Created: 2011-05-16 Last updated: 2018-06-08Bibliographically approved
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