Aggregation of alpha-synuclein: A structural study via cryo-electron microscopy
Abstract
The aggregation of alpha-synuclein is thought to play a role in the death of dopaminergic neurons in Parkinson's disease (PD). Alpha-synuclein transitions through an aggregation pathway consisting of intermediate species referred to as protofibrils (or oligomer), which ultimately convert to mature fibrils. There is controversy in the field over the question of which species are toxic. Furthermore, the structural heterogeneity and instability of protofibrils has significantly impeded advance related to the understanding of their structural characteristics and the amyloid aggregation mystery. Here, we report, for the first time, on alpha-synuclein protofibril structural characteristics with cryo-electron microscopy (cryo-EM). Statistical analysis of annular protofibrils revealed a constant wall thickness as a common feature. The visualization of assembly steps enabled us to propose a novel mechanisms for alpha-synuclein aggregation involving ring-opening and protofibril-protofibril interaction events. Moreover, environmental Cu(II), which significantly enhanced the toxicity of alpha-synuclein aggregates to mammalian dopaminergic neurons, was found to promote in vitro aggregation by facilitating annular protofibril formation rather than fibril formation. This result strongly supports the hypothesis that annular protofibrils are the toxic species. The ion channel-like protofibrils and their membrane permeability have also been found in other amyloid diseases, suggesting a common molecular mechanism of pathological aggregation. Our direct visualization of the aggregation pathway of alpha-synuclein opens up novel opportunities to advance the understanding of protein aggregation mechanisms relevant to many amyloid diseases. In turn, this information would enable the development of novel therapeutic strategies aimed at suppressing toxic protofibrils of amyloid proteins involved in neurological disorders.
Degree
Ph.D.
Advisors
Jiang, Purdue University.
Subject Area
Biochemistry|Biomedical engineering|Biophysics
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