Journal
JOURNAL OF PARKINSONS DISEASE
Volume 7, Issue 3, Pages 433-450Publisher
IOS PRESS
DOI: 10.3233/JPD-171103
Keywords
alpha-synuclein; amyloid; cholesterol; fatty acids; glucocerebrosidase; kinetic analysis; lipids; Parkinson's disease; sphingolipid
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Funding
- Alexander von Humboldt Foundation
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alpha-synuclein is a small protein abundantly expressed in the brain and mainly located in synaptic terminals. The conversion of alpha-synuclein into oligomers and fibrils is the hallmark of a range of neurodegenerative disorders including Parkinson's disease and dementia with Lewy bodies. alpha-synuclein is disordered in solution but can adopt an alpha-helical conformation upon binding to lipid membranes. This lipid-protein interaction plays an important role in its proposed biological function, i.e., synaptic plasticity, but can also entail the aggregation of the protein. Both the chemical properties of the lipids and the lipid-to-protein-ratio have been reported to modulate the aggregation propensity of alpha-synuclein. In this review, the influence of changes in the nature and levels of lipids on the aggregation propensity of alpha-synuclein in vivo and in vitro will be discussed within a common general framework. In particular, while biophysical measurements and kinetic analyses of the time courses of alpha-synuclein aggregation in the presence of different types of lipid vesicles allow a mechanistic dissection of the influence of the lipids on alpha-synuclein aggregation, biological studies of cellular and animal models of Parkinson's disease allow the determination of changes in lipid levels and properties associated with the disease.
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