α-Synuclein misfolding and aggregation: Implications in Parkinson's disease pathogenesis.

Authors:
Surabhi Mehra
Surabhi Mehra
Department of Biosciences and Bioengineering
Shruti Sahay
Shruti Sahay
Indian Institute of Technology Bombay
India
Samir K Maji
Samir K Maji
Indian Institute of Technology Madras
India

Biochim Biophys Acta Proteins Proteom 2019 Mar 7. Epub 2019 Mar 7.

Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India. Electronic address:

α-Synuclein (α-Syn) has been extensively studied for its structural and biophysical properties owing to its pathophysiological role in Parkinson's disease (PD). Lewy bodies and Lewy neurites are the pathological hallmarks of PD and contain α-Syn aggregates as their major component. It was therefore hypothesized that α-Syn aggregation is actively associated with PD pathogenesis. The central role of α-Syn aggregation in PD is further supported by the identification of point mutations in α-Syn protein associated with rare familial forms of PD. However, the correlation between aggregation propensities of α-Syn mutants and their association with PD phenotype is not straightforward. Recent evidence suggested that oligomers, formed during the initial stages of aggregation, are the potent neurotoxic species causing cell death in PD. However, the heterogeneous and unstable nature of these oligomers limit their detailed characterization. α-Syn fibrils, on the contrary, are shown to be the infectious agents and propagate in a prion-like manner. Although α-Syn is an intrinsically disordered protein, it exhibits remarkable conformational plasticity by adopting a range of structural conformations under different environmental conditions. In this review, we focus on the structural and functional aspects of α-Syn and role of potential factors that may contribute to the underlying mechanism of synucleinopathies. This information will help to identify novel targets and develop specific therapeutic strategies to combat Parkinson's and other protein aggregation related neurodegenerative diseases.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbapap.2019.03.001DOI Listing

Still can't find the full text of the article?

We can help you send a request to the authors directly.
March 2019

Publication Analysis

Top Keywords

α-syn
9
α-syn aggregation
8
parkinson's disease
8
aggregation
6
formed initial
4
factors contribute
4
cell death
4
oligomers formed
4
suggested oligomers
4
contribute underlying
4
initial stages
4
stages aggregation
4
neurotoxic species
4
species causing
4
role potential
4
potent neurotoxic
4
potential factors
4
aggregation potent
4
evidence suggested
4
causing cell
4

Similar Publications