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- Title
A novel, high-efficiency cellular model of fibrillar α-synuclein inclusions and the examination of mutations that inhibit amyloid formation.
- Authors
Waxman, Elisa A.; Giasson, Benoit I.
- Abstract
J. Neurochem. (2010) 113, 374–388. Intracytoplasmic alpha-synuclein (α-syn) amyloidogenic inclusions are a major pathological feature of Parkinson’s disease, dementia with Lewy body disease and multiple systems atrophy. The mechanisms involved in the formation and inhibition of these aggregates are areas of intense investigation. The present study characterizes a novel cellular model for the study of α-syn aggregation, incorporating nucleation-dependent aggregation and a new function for calcium phosphate precipitation. Cultured cells were readily induced to develop large, cytoplasmic α-syn filamentous aggregates that were hyperphosphorylated, often ubiquitinated and thioflavin positive. These cellular aggregates formed in the majority of transfected cells and recruited approximately half of endogenously expressed α-syn. Using this system, we examined single-point mutations that inhibit α-syn amyloid formation in vitro. Three mutations (V66P, T72P and T75P) significantly hindered α-syn aggregation in this cell model. The T75P mutant, which could abrogate amyloid formation of wild-type α-syn in vitro, did not prevent wild-type α-syn cellular aggregates. These studies suggest that the propensity of α-syn to form cellular aggregates may be more pronounced than in isolated in vitro studies. This novel high-efficiency cellular model of α-syn aggregation is a valuable system that may be used to further understand α-syn aggregation and allow for the generation of future therapeutics.
- Subjects
PARKINSON'S disease; EXTRAPYRAMIDAL disorders; BRAIN diseases; CELLS; GLYCOPROTEINS
- Publication
Journal of Neurochemistry, 2010, Vol 113, Issue 2, p374
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2010.06592.x