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Fahmy, N., Müller, K., Andersen, P. M., Marklund, S. L., Otto, M., Ludolph, A. C. & Hamdi, N. (2023). A novel homozygous p.Ser69Pro SOD1 mutation causes severe young-onset ALS with decreased enzyme activity. Journal of Neurology, 270, 1770-1773
Open this publication in new window or tab >>A novel homozygous p.Ser69Pro SOD1 mutation causes severe young-onset ALS with decreased enzyme activity
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2023 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 270, p. 1770-1773Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Enzyme activity, Homozygous, Novel mutation, SOD1, Young-onset
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-201750 (URN)10.1007/s00415-022-11489-x (DOI)000894540900004 ()36472686 (PubMedID)2-s2.0-85143510425 (Scopus ID)
Available from: 2022-12-30 Created: 2022-12-30 Last updated: 2023-06-29Bibliographically approved
Tsioras, K., Smith, K. C., Edassery, S. L., Garjani, M., Li, Y., Williams, C., . . . Kiskinis, E. (2023). Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis. Cell Reports, 42(10), Article ID 113160.
Open this publication in new window or tab >>Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis
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2023 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 10, article id 113160Article in journal (Refereed) Published
Abstract [en]

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
ALS, amyotrophic lateral sclerosis, CP: Neuroscience, CP: Stem cell research, iPSCs, motor neurons, protein degradation, SILAC-based mass spectrometry, SOD1, ubiquitin, VCP/p97
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:umu:diva-215749 (URN)10.1016/j.celrep.2023.113160 (DOI)37776851 (PubMedID)2-s2.0-85174155270 (Scopus ID)
Funder
NIH (National Institutes of Health)Swedish Research Council, 2019-01634
Available from: 2023-11-02 Created: 2023-11-02 Last updated: 2024-01-17Bibliographically approved
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
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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
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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
Forsberg, K., Graffmo, K. S., Stenvall, E., Tabikh, N., Marklund, S. L., Brännström, T. & Andersen, P. M. (2023). Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation. Acta Neuropathologica, 145(1), 13-28
Open this publication in new window or tab >>Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation
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2023 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 145, no 1, p. 13-28Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Springer-Verlag New York, 2023
Keywords
Amyotrophic lateral sclerosis, D90A, Human autopsy, Neuronal inclusions, Superoxide dismutase-1
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-201353 (URN)10.1007/s00401-022-02519-z (DOI)000884616800001 ()36385230 (PubMedID)2-s2.0-85142073549 (Scopus ID)
Funder
The Swedish Brain Foundation, 2012- 0262The Swedish Brain Foundation, 2012-0305The Swedish Brain Foundation, 2013-0279The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2019-0320The Swedish Brain Foundation, 2020-0353The Swedish Brain Foundation, 2021-0402Swedish Research Council, 2009-3548Swedish Research Council, 2012-3167Swedish Research Council, 2017-03100Swedish Research Council, 2019-01707Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, d 2020.0232The Kempe FoundationsRegion Västerbotten, 2013-7590Region Västerbotten, 56103-7002829Region Västerbotten, RV-841161Region Västerbotten, RV-833421Region Västerbotten, RV-932195Region Västerbotten, RV-939329Region Västerbotten, RV-941598Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Available from: 2022-12-08 Created: 2022-12-08 Last updated: 2023-01-11Bibliographically approved
Günther, R., Pal, A., Williams, C., Zimyanin, V. L., Liehr, M., von Neubeck, C., . . . Hermann, A. (2022). Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS. Cells, 11(7), Article ID 1246.
Open this publication in new window or tab >>Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
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2022 (English)In: Cells, E-ISSN 2073-4409, Vol. 11, no 7, article id 1246Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
ALS1, axonal trafficking, live cell imaging, mitochondria, SOD1
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-193795 (URN)10.3390/cells11071246 (DOI)000781321900001 ()35406813 (PubMedID)2-s2.0-85127602913 (Scopus ID)
Funder
Swedish Research Council, VR-MH 2019-01634
Available from: 2022-05-06 Created: 2022-05-06 Last updated: 2023-03-24Bibliographically approved
Ezer, S., Daana, M., Park, J. H., Yanovsky-Dagan, S., Nordström, U., Basal, A., . . . Harel, T. (2022). Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity. Brain, 145(3), 872-878
Open this publication in new window or tab >>Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity
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2022 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 145, no 3, p. 872-878Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Oxford University Press, 2022
Keywords
amyotrophic lateral sclerosis, exome sequencing, SOD1, superoxide dismutase
National Category
Neurology Neurosciences Medical Genetics
Identifiers
urn:nbn:se:umu:diva-194841 (URN)10.1093/brain/awab416 (DOI)000767441400001 ()34788402 (PubMedID)2-s2.0-85129780082 (Scopus ID)
Available from: 2022-06-01 Created: 2022-06-01 Last updated: 2022-06-01Bibliographically approved
Keskin, I., Ekhtiari Bidhendi, E., Marklund, M., Andersen, P. M., Brännström, T., Marklund, S. L. & Nordström, U. (2021). Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice. Acta neuropathologica communications, 9(1), Article ID 111.
Open this publication in new window or tab >>Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice
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2021 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 9, no 1, article id 111Article in journal (Refereed) Published
Abstract [en]

The deposition of aggregated proteins is a common neuropathological denominator for neurodegenerative disorders. Experimental evidence suggests that disease propagation involves prion-like mechanisms that cause the spreading of template-directed aggregation of specific disease-associated proteins. In transgenic (Tg) mouse models of superoxide dismutase-1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), inoculation of minute amounts of human SOD1 (hSOD1) aggregates into the spinal cord or peripheral nerves induces premature ALS-like disease and template-directed hSOD1 aggregation that spreads along the neuroaxis. This infectious nature of spreading pathogenic aggregates might have implications for the safety of laboratory and medical staff, recipients of donated blood or tissue, or possibly close relatives and caregivers. Here we investigate whether transmission of ALS-like disease is unique to the spinal cord and peripheral nerve inoculations or if hSOD1 aggregation might spread from the periphery into the central nervous system (CNS). We inoculated hSOD1 aggregate seeds into the peritoneal cavity, hindlimb skeletal muscle or spinal cord of adult Tg mice expressing mutant hSOD1. Although we used up to 8000 times higher dose—compared to the lowest dose transmitting disease in spinal cord inoculations—the peripheral inoculations did not transmit seeded aggregation to the CNS or premature ALS-like disease in hSOD1 Tg mice. Nor was any hSOD1 aggregation detected in the liver, kidney, skeletal muscle or sciatic nerve. To explore potential reasons for the lack of disease transmission, we examined the stability of hSOD1 aggregates and found them to be highly vulnerable to both proteases and detergent. Our findings suggest that exposed individuals and personnel handling samples from ALS patients are at low risk of any potential transmission of seeded hSOD1 aggregation.

Place, publisher, year, edition, pages
BioMed Central, 2021
Keywords
Aggregate stability, ALS, Amyotrophic lateral sclerosis, Peripheral administration, Prion-like, Protein aggregation, SOD1, Superoxide dismutase 1
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-185894 (URN)10.1186/s40478-021-01211-9 (DOI)000665853700001 ()34158126 (PubMedID)2-s2.0-85109055645 (Scopus ID)
Funder
The Swedish Brain Foundation, 2015-0234The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2019-0320The Swedish Brain Foundation, 2020-0353Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232
Available from: 2021-07-12 Created: 2021-07-12 Last updated: 2021-07-12Bibliographically 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
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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
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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
Projects
Studies of enzymes metabolizing the toxic reduction products of oxygen the superoxide anion radical and hydrogen peroxide [2009-04942_VR]; Umeå UniversityMolecular structure of superoxide dismutase aggregates and pathogeneisis of amyotrophic lateral sclerosis [2012-01821_VR]; Umeå UniversityALS caused by strains of SOD1 prions [2015-02804_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3270-2854

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