Aggregation-defective alpha-synuclein mutants inhibit the fibrillation of Parkinson's disease-linked alpha-synuclein variants.
Alpha-synuclein comprises the fibrillar core of Lewy bodies, which is one of the histologically defining lesions of Parkinson's disease. Previously, we screened for alpha-synuclein substitution mutants that do not form fibrils. For preventative or therapeutic uses, it is essential to suppress the oligomerization/fibrillation of the wild-type and PD-linked alpha-synuclein proteins. Here we have examined the effects of fibrillation-retarded alpha-synuclein mutants on fibril formation by wild-type and PD-linked alpha-synuclein molecules. Six self-aggregation-defective alpha-synuclein mutants completely inhibit the fibrillation of both wild-type and Parkinson's disease-linked alpha-synuclein variants. These results suggest future applications for gene therapy: the transplantation of a fibrillation-blocking mutant alpha-synuclein gene into individuals who carry an early-onset PD-associated alpha-synuclein allele. Short synthetic peptides derived from these mutant sequences may also serve as a lead compound for the development of therapeutics for Parkinson's disease.
Koo
Hyun-Jung
HJ
Department of Molecular Biology, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea.
Choi
Min Yeong
MY
Im
Hana
H
D000682:Amyloid / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism* / Q000628:therapy; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D051844:alpha-Synuclein