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Mutant superoxide d...
Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis
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- Ekhtiari Bidhendi, Elaheh (författare)
- Umeå universitet,Patologi,ALS-gruppen
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- Bergh, Johan, 1983- (författare)
- Umeå universitet,Patologi,ALS-gruppen
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- Zetterström, Per (författare)
- Umeå universitet,Klinisk kemi,ALS-gruppen
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- Forsberg, Karin (författare)
- Umeå universitet,Patologi,ALS-gruppen
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Pakkenberg, Bente (författare)
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- Andersen, Peter M., 1962- (författare)
- Umeå universitet,Klinisk neurovetenskap
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- Marklund, Stefan L. (författare)
- Umeå universitet,Klinisk kemi
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- Brännström, Thomas (författare)
- Umeå universitet,Patologi
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(creator_code:org_t)
- 2018-10-03
- 2018
- Engelska.
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Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 136:6, s. 939-953
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Superoxide dismutase
- prion-like
- aggregation
- propagation
- motor neuron disease
- neurologi
- Neurology
- patologi
- Pathology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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