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Brännström, Thomas
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Publications (10 of 100) Show all publications
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
Björkblom, B., Wibom, C., Eriksson, M., Bergenheim, A. T., Sjöberg, R. L., Jonsson, P., . . . Melin, B. S. (2022). Distinct metabolic hallmarks of WHO classified adult glioma subtypes. Neuro-Oncology, 24(9), 1454-1468, Article ID noac042.
Open this publication in new window or tab >>Distinct metabolic hallmarks of WHO classified adult glioma subtypes
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2022 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 24, no 9, p. 1454-1468, article id noac042Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Gliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy.

METHODS: Cross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors - oligodendroglioma (n=31), astrocytoma (n=31) and glioblastoma (n=162) - were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2-4, and MGMT promoter methylation.

RESULTS: Distinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue.

CONCLUSION: Key metabolic differences exist across adult glioma subtypes.

Place, publisher, year, edition, pages
Oxford University Press, 2022
Keywords
Astrocytoma, Glioblastoma, Metabolic reprogramming, Oligodendroglioma, WHO classification
National Category
Cancer and Oncology
Research subject
Molecular Biology; Pathology; Oncology
Identifiers
urn:nbn:se:umu:diva-192529 (URN)10.1093/neuonc/noac042 (DOI)000785708300001 ()35157758 (PubMedID)2-s2.0-85137137374 (Scopus ID)
Funder
Swedish Cancer Society, 2018/390Swedish Cancer Society, 2013/0291Swedish Cancer Society, 19 0370Swedish Research Council, 2019-01566Cancerforskningsfonden i Norrland, AMP17-899Cancerforskningsfonden i Norrland, AMP17- 882Sjöberg Foundation, 2020-01-07-08
Available from: 2022-05-17 Created: 2022-05-17 Last updated: 2023-05-23Bibliographically approved
Masrori, P., Ospitalieri, S., Forsberg, K., Moens, T. G., Poesen, K., Race, V., . . . Van Damme, P. (2022). Respiratory onset of amyotrophic lateral sclerosis in a pregnant woman with a novel SOD1 mutation. European Journal of Neurology, 29(4), 1279-1283
Open this publication in new window or tab >>Respiratory onset of amyotrophic lateral sclerosis in a pregnant woman with a novel SOD1 mutation
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2022 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 29, no 4, p. 1279-1283Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), the importance of gene testing in ALS is increasing. This will likely lead to the identification of new variants for which the pathogenicity is not established. We aimed to study the pathogenicity of a newly identified variant in superoxide dismutase 1 (SOD1).

METHODS: Gene testing was performed using Sanger sequencing. SOD1 activity in erythrocytes was measured using spectrophotometry. Postmortem brain and spinal cord sections were stained with antibodies against phospho-TDP-43 and SOD1.

RESULTS: We identified a novel c.416G>T (p.Gly139Val) mutation in SOD1, which caused a rapidly progressive respiratory onset form of ALS. The mutation resulted in a 50% drop of SOD1 activity. Postmortem examination confirmed the absence of TDP-43 pathology and displayed typical SOD1 inclusions in remaining motor neurons, confirming the pathogenic nature of the mutation.

CONCLUSIONS: Novel variants of unknown pathogenicity will be identified as a result of a surge in gene testing in people with ALS. An in-depth study of a newly identified p.Gly139Val mutation in SOD1 confirmed the pathogenicity of this mutation. Future patients with this particular mutation should qualify for SOD1 silencing or editing therapies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
antisense oligonucleotides, gene silencing, novel mutation, respiratory onset of ALS, SOD1
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-193155 (URN)10.1111/ene.15224 (DOI)000765395700038 ()35253968 (PubMedID)2-s2.0-85125880986 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Swedish Research Council, 2017-03100The Swedish Brain Foundation, 2020-0353
Available from: 2022-03-22 Created: 2022-03-22 Last updated: 2022-03-22Bibliographically 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., Graffmo, K. S., Pakkenberg, B., Weber, M., Nielsen, M., Marklund, S. L., . . . Andersen, P. M. (2019). Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes. Journal of Neurology, Neurosurgery and Psychiatry, 90(8), 861-869
Open this publication in new window or tab >>Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes
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2019 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 8, p. 861-869Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
Keywords
amyotrophic lateral sclerosis, neuronal inclusions, C9orf72, KIF5A, superoxide dismutase-1
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-163689 (URN)10.1136/jnnp-2018-319386 (DOI)000482509400004 ()30992335 (PubMedID)2-s2.0-85062953488 (Scopus ID)
Available from: 2019-10-17 Created: 2019-10-17 Last updated: 2023-06-21Bibliographically approved
Brännström, T., Andersen, P. M., Bergh, J., Ekhtiari Bidhendi, E. & Marklund, S. M. (2019). Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease. Paper presented at 19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN. Brain Pathology, 29, 90-90
Open this publication in new window or tab >>Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease
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2019 (English)In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 29, p. 90-90Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2019
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-157592 (URN)000459814800279 ()
Conference
19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN
Note

Supplement: 1

Special Issue: SI

Meeting Abstract: P2-66

Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-11-25Bibliographically approved
Wu, W.-Y. Y., Johansson, G., Wibom, C., Brännström, T., Malmström, A., Henriksson, R., . . . Melin, B. S. (2019). The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes. Cancers, 11(12), Article ID 2001.
Open this publication in new window or tab >>The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 12, article id 2001Article, review/survey (Refereed) Published
Abstract [en]

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
glioma, IDH mutant, 1p/19q co-deletion, gliomagenesis, genotype phenotype, etiopathogenesis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-167615 (URN)10.3390/cancers11122001 (DOI)000507382100178 ()31842352 (PubMedID)2-s2.0-85076550363 (Scopus ID)
Available from: 2020-02-06 Created: 2020-02-06 Last updated: 2020-04-08Bibliographically 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)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
Tjust, A. E., Danielsson, A., Andersen, P. M., Brännstrom, T. & Pedrosa-Domellöf, F. (2017). Impact of Amyotrophic Lateral Sclerosis on Slow Tonic Myofiber Composition in Human Extraocular Muscles. Investigative Ophthalmology and Visual Science, 58(9), 3708-3715
Open this publication in new window or tab >>Impact of Amyotrophic Lateral Sclerosis on Slow Tonic Myofiber Composition in Human Extraocular Muscles
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2017 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 58, no 9, p. 3708-3715Article in journal (Refereed) Published
Abstract [en]

PURPOSE. To analyze the proportion and cross-sectional area of myofibers containing myosin heavy chain slow-twitch (MyHCI) and myosin heavy chain slow tonic (MyHCsto) in extraocular muscles of autopsied amyotrophic lateral sclerosis (ALS) patients with either spinal or bulbar site of disease onset. METHODS. Whole-muscle cross sections from the middle portion of the medial rectus were labeled with antibodies against MyHCI or MyHCsto and laminin. Myofibers labeled with the MyHC antibodies (MyHCI+sto) and the total number of myofibers were quantified in the orbital and global layer of 6 control individuals and 18 ALS patients. The cross-sectional area of myofibers labeled for either MyHC was quantified in 130 to 472 fibers/individual in the orbital and in 180 to 573 fibers/individual in the global layer of each specimen. RESULTS. The proportion of MyHCI+sto myofibers was significantly smaller in the orbital and global layer of ALS compared to control individuals. MyHCI+sto myofibers were significantly smaller in the global layer than in the orbital layer of ALS, whereas they were of similar size in control subjects. The decreased proportion of MyHCI+sto fibers correlated significantly with the age of death, but not disease duration, in patients who had the bulbar-onset variant of ALS but not in patients with spinal variant. CONCLUSIONS. ALS, regardless of site of onset, involves a loss of myofibers containing MyHCI+sto. Only in bulbar-onset cases did aging seem to play a role in the pathophysiological processes underlying the loss of MyHCI+sto fibers.

Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2017
Keywords
amyotrophic lateral sclerosis, extraocular muscles, MyH14, slow tonic, muscle fibers
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-140482 (URN)10.1167/iovs.17-22098 (DOI)000410931200051 ()28738414 (PubMedID)2-s2.0-85026313703 (Scopus ID)
Available from: 2017-10-20 Created: 2017-10-20 Last updated: 2023-06-26Bibliographically approved
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