Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis
Abstract
Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease. Autosomal dominant mutations in the SOD1 gene are responsible for 12% of familial ALS cases and 1.5% of sporadic cases. However, it remains unknown whether the large fibrillar aggregates formed by misfolded SOD1 are a causative agent in disease progression. By designing mutations that specifically stabilize SOD1 fibrils or nonnative oligomers, we found that the assembly into insoluble fibrils mitigated the neurotoxic effects caused by aberrant conformation of trimers. We also demonstrated with electron microscopy that toxic SOD1 trimers displayed heterogeneous structures, in concert with computational studies. Our findings suggest a protective role of fibrils and a plausible pharmaceutical strategy, as promoting SOD1 fibrillogenesis reduces the population of neurotoxic species.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- May 2018
- DOI:
- 10.1073/pnas.1800187115
- Bibcode:
- 2018PNAS..115.4661Z