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(The FASEB Journal. 2004;18:617-626.)
© 2004 FASEB

{alpha}-Synuclein and Parkinson’s disease

ALESSANDRA RECCHIA1, PATRIZIA DEBETTO1, ALESSANDRO NEGRO*, DIEGO GUIDOLIN{dagger}, STEPHEN D. SKAPER{ddagger} and PIETRO GIUSTI2

Department of Pharmacology and Anesthesiology,
* "Centro di Ricerche in Biotecnologie Innovative,"
{dagger} Department of Human Anatomy and Physiology, University of Padova, 35131 Padova, Italy; and
{ddagger} Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, Harlow, Essex CM19 5AW, U.K.

2Correspondence: Department of Pharmacology and Anesthesiology, L.go Meneghetti, 2, 35131 Padova, Italy. E-mail: pietro.giusti{at}unipd.it

Alpha-synuclein ({alpha}-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. Interest in {alpha}-syn has increased dramatically after the discovery of a relationship between its dysfunction and several neurodegenerative diseases, including Parkinson’s disease (PD). The physiological functions of {alpha}-syn remain to be fully defined, although recent data suggest a role in regulating membrane stability and neuronal plasticity. Various trigger factors, either environmental or genetic, can lead to a cascade of events involving misfolding or loss of normal function of {alpha}-syn. In dopaminergic neurons, this may promote a vicious cycle in which elevation in cytoplasmic dopamine, oxidative stress, {alpha}-syn dysfunction, and disruption of vesicle function lead to dopaminergic cell loss and PD. {alpha}-Syn dysfunction appears to be a common feature of all forms of PD. The mechanism by which {alpha}-syn induces neuronal cell toxicity may invoke multiple pathways, such as aggregation or interaction with other proteins and molecules, including synphilin-1, chaperone 14-3-3 protein, and dopamine itself. This complexity has hindered the development of models to study PD. The available animal models of PD, each present distinct advantages and limits. Findings to date suggest that {alpha}-syn-based models represent a paradigm, which is closest to the human pathology.—Recchia, A., Debetto, P., Negro, A., Guidolin, D., Skaper, S. D., Giusti, P. {alpha}-Synuclein and Parkinson’s disease.


Key Words: {alpha}-synuclein aggregation • dopaminergic neurons • animal models of Parkinson’s disease




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