Abstract
α-Synuclein (α-Syn) aggregation is directly associated with Parkinson’s disease (PD) pathogenesis. In vitro aggregation and in vivo animal model studies of α-Syn recapitulate many features of the disease pathogenesis. Six familial PD associated mutations of α-Syn have been discovered; many of which are associated with early onset PD. Three of PD associated mutations have been shown to accelerate the α-Syn aggregation, whereas other three are shown to delay the aggregation kinetics. The membrane binding studies also suggest that few of these PD mutants strongly bind to synthetic membrane vesicles, while others are shown to have attenuated membrane binding ability. Furthermore, the PD mutations do not drastically alter the toxicity of α-Syn oligomers/fibrils. Although according to recent suggestions that early formed oligomers are the most potent toxic species responsible for PD, only p.A30P mutant is shown to form faster oligomers and delayed conversion from oligomers to fibrils. Therefore, it is difficult to establish a unifying mechanism of how familial PD associated mutations affect the α-Syn structure, aggregation and function for their disease association. It is possible that each PD associated mutation alters α-Syn biology in a unique way, which might be responsible for disease pathogenesis. In this review, we discuss the structure function of α- Syn and how these are altered due to the PD associated mutations and their relationship to disease pathogenesis.
Keywords: α-Synuclein, amyloid fibrils, autosomal dominant parkinsonism, dementia with Lewy bodies, genomic multiplication, neurodegeneration, prion-like features, protein misfolding.
Graphical Abstract
Related Journals
Protein & Peptide Letters
Related Books
Frontiers in Protein and Peptide Sciences
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