Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Zetterström, Per
Publications (10 of 23) Show all publications
Nordström, U., Lang, L., Ekhtiari Bidhendi, E., Zetterström, P., Oliveberg, M., Danielsson, J., . . . Marklund, S. L. (2023). Mutant SOD1 aggregates formed in vitro and in cultured cells are polymorphic and differ from those arising in the CNS. Journal of Neurochemistry, 164(1), 77-93
Open this publication in new window or tab >>Mutant SOD1 aggregates formed in vitro and in cultured cells are polymorphic and differ from those arising in the CNS
Show others...
2023 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 164, no 1, p. 77-93Article in journal (Refereed) Published
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.)

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
aggregate structure, ALS, amyotrophic lateral sclerosis, neurodegenerative disease, superoxide dismutase 1, protein misfolding, protein aggregation, aggregate strains, aggregate conformation
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-201477 (URN)10.1111/jnc.15718 (DOI)000890056900001 ()36326589 (PubMedID)2-s2.0-85142644226 (Scopus ID)
Funder
The Swedish Brain Foundation, 2013-0279The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2020-0353The Kempe FoundationsKnut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Konung Gustaf V:s och Drottning Victorias FrimurarestiftelseSwedish Association of Persons with Neurological DisabilitiesTorsten Söderbergs stiftelseUmeå University, 2.1.12-1605-14Umeå University, 223-1881-13Umeå University, 223-2808-12Region Västerbotten, 56103- 7002829Swedish Research Council, 2017-03100Swedish Research Council, 2012-3167
Available from: 2022-12-06 Created: 2022-12-06 Last updated: 2023-01-11Bibliographically approved
Park, J. H., Nordström, U., Tsiakas, K., Keskin, I., Elpers, C., Mannil, M., . . . Andersen, P. M. (2023). The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1. Brain Communications, 5(1), Article ID fcad017.
Open this publication in new window or tab >>The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1
Show others...
2023 (English)In: Brain Communications, E-ISSN 2632-1297, Vol. 5, no 1, article id fcad017Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
ALS, infantile motor neuron disease, oxygen toxicity, SOD1, spasticity
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-208224 (URN)10.1093/braincomms/fcad017 (DOI)000929911200001 ()36793789 (PubMedID)2-s2.0-85153953022 (Scopus ID)
Funder
The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2020-0353Swedish Research Council, 2017-03100Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Umeå UniversityRegion VästerbottenKonung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Available from: 2023-05-12 Created: 2023-05-12 Last updated: 2023-05-12Bibliographically approved
Lehmann, M., Marklund, M., Bolender, A.-L., Bidhendi, E. E., Zetterström, P., Andersen, P. M., . . . Nordström, U. (2020). Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice. Acta neuropathologica communications, 8(1), Article ID 161.
Open this publication in new window or tab >>Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice
Show others...
2020 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 8, no 1, article id 161Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BMC, 2020
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-157035 (URN)10.1186/s40478-020-01032-2 (DOI)000570828300001 ()32928301 (PubMedID)2-s2.0-85091051811 (Scopus ID)
Note

Originally published in thesis in manuscript form with title: "An aggregate-selective monoclonal antibody attenuates seeded but not spontaneously evolving SOD1 aggregation in ALS model mice" and authors: "Manuela Lehmann, Matthew Marklund, Anna-Lena Bolender, Elaheh E. Bidhendi, Anders Olofsson, Peter M. Andersen, Thomas Brännström, Stefan L. Marklund, Jonathan D. Gilthorpe, Ulrika Nordström"

Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2023-03-24Bibliographically approved
Forsberg, K., Tjust, A. E., Zetterström, P., Marklund, S. L. & Andersen, P. M. (2020). ALS kan vara en prionsjukdom: Inklusioner av felvecklat SOD1-protein tycks finnas hos patienter med alla typer av ALS. Läkartidningen, 117, Article ID FYT4.
Open this publication in new window or tab >>ALS kan vara en prionsjukdom: Inklusioner av felvecklat SOD1-protein tycks finnas hos patienter med alla typer av ALS
Show others...
2020 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 117, article id FYT4Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Läkartidningen Förlag AB, 2020
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-179759 (URN)32154903 (PubMedID)2-s2.0-85081929668 (Scopus ID)
Note

Lakartidningen.se 2020-03-10

Available from: 2021-02-09 Created: 2021-02-09 Last updated: 2023-06-26Bibliographically approved
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
Show others...
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)2-s2.0-85070850141 (Scopus ID)
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2023-03-23Bibliographically 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
Show others...
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)2-s2.0-85062973445 (Scopus ID)
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: 2023-03-24Bibliographically 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
Show others...
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)2-s2.0-85054524158 (Scopus ID)
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: 2023-03-24Bibliographically 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
Show others...
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)2-s2.0-84974653241 (Scopus ID)
Available from: 2016-07-25 Created: 2016-06-20 Last updated: 2023-03-24Bibliographically 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
Show others...
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)2-s2.0-84938920150 (Scopus ID)
Available from: 2015-09-18 Created: 2015-09-04 Last updated: 2023-03-24Bibliographically 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
Show others...
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)2-s2.0-84928779088 (Scopus ID)
Available from: 2015-05-28 Created: 2015-05-18 Last updated: 2023-03-23Bibliographically approved
Organisations

Search in DiVA

Show all publications