Current Protein & Peptide Science

Ben M. Dunn  
Department of Biochemistry and Molecular Biology University of Florida
College of Medicine, P.O. Box 100245, Gainesville
Florida, FL 32610-0245
USA

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Enhanced α-Synuclein Expression in Human Neurodegenerative Diseases: Pathogenetic and Therapeutic Implications

Author(s): Alison L. McCormack, Donato A. Di Monte.

Abstract:

When caused by multiplication mutations of its gene, increased expression of α-synuclein is associated with familial parkinsonism. Here we discuss the possibility that other mechanisms of α-synuclein elevation contribute to the pathogenesis of idiopathic, sporadic Parkinsons disease and other human synucleinopathies. Environmental (e.g. toxic exposures) and genetic (e.g. gene polymorphisms) risk factors, on the background of normal aging, are likely to enhance vulnerability to neurodegenerative processes. Current evidence suggests that an increased level of neuronal α-synuclein may represent a key pathogenetic event common to these risk factors. Higher protein expression could underlie a gain of toxic properties of α-synuclein (e.g. enhanced tendency to aggregate) that predispose and/or directly contribute to neuronal demise. An important corollary to this latter concept is that a promising therapeutic approach against Parkinsons and other neurodegenerative diseases is to prevent α-synuclein accumulation. Means to achieve this include (i) the use of RNA interference to suppress α-synuclein expression, (ii) the induction of neuronal pathways of protein degradation (e.g. macroautophagy) involved in α-synuclein clearance, and (iii) the development of anti-aggregation agents counteracting the formation of toxic oligomeric or fibrillar forms of the protein.

Keywords: α-synuclein, Parkinson's disease, substantia nigra, aggregation, neurotoxins, aging, RNA interference, autophagy

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Article Details

VOLUME: 10
ISSUE: 5
Year: 2009
Page: [476 - 482]
Pages: 7
DOI: 10.2174/138920309789351912
Price: $58