Biophysics of Parkinson's Disease: Structure and Aggregation of α- Synuclein
Document Type
Article
Publication Date
2009
Keywords
NMR, Aggregation, Amyloid, Fibril, Intrinsically Disordered Protein, Neurodegeneration, Partially Folded Intermediate, Synucleinopathies, α-synuclein
Digital Object Identifier (DOI)
https://doi.org/10.2174/138920309789351921
Abstract
Parkinson's disease (PD) is a slowly progressive movement disorder that results from the loss of dopaminergic neurons in the substantia nigra, a small area of cells in the mid-brain. PD is a multifactorial disorder with unknown etiology, in which both genetic and environmental factors play important roles. Substantial evidence links α-synuclein, a small highly conserved presynaptic protein with unknown function, to both familial and sporadic PD. Rare familial cases of PD are associated with missense point mutations in α-synuclein, or with the hyper-expression of the wild type protein due to its gene duplication/triplication. Furthermore, α-synuclein was identified as the major component of amyloid fibrils found in Lewy body and Lewy neurites, the characteristic proteinaceous deposits that are the diagnostic hallmarks of PD. α- Synuclein is abundant in various regions of the brain and has two closely related homologs, β-synuclein and γ-synuclein. When isolated in solution, the protein is intrinsically disordered, but in the presence of lipid surfaces α-synuclein adopts a highly helical structure that is believed to mediate its normal function(s). A number of different conformational states of α-synuclein have been observed. Besides the membrane-bound form, other critical conformations include a partiallyfolded state that is a key intermediate in aggregation and fibrillation, various oligomeric species, and fibrillar and amorphous aggregates. A number of intrinsic and extrinsic factors that either accelerate or inhibit the rate of α-synuclein aggregation and fibrillation in vitro are known. There is a strong correlation between the conformation of α-synuclein (induced by various factors) and its rate of fibrillation. The aggregation process appears to be branched, with one pathway leading to fibrils and another to oligomeric intermediates that may ultimately form amorphous deposits. The molecular basis of Parkinson's disease appears to be tightly coupled to the aggregation of α-synuclein and the factors that affect its conformation. This review focuses on the contributions of Prof. Anthony L. Fink to the field and presents some recent developments in this exciting area.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Current Protein and Peptide Science, v. 10, issue 5, p. 483-499
Scholar Commons Citation
Uversky, Vladimir N. and Eliezer, David, "Biophysics of Parkinson's Disease: Structure and Aggregation of α- Synuclein" (2009). Molecular Medicine Faculty Publications. 569.
https://digitalcommons.usf.edu/mme_facpub/569
