The role of alpha-synuclein in neurodegenerative diseases.
Alpha-synuclein is a 140 amino acid neuronal protein that has been associated with several neurodegenerative diseases. A point mutation in the gene coding for the alpha-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson's disease (PD). Subsequently, other mutations in the alpha-synuclein gene have been identified in familial PD. The aggregated proteinaceous inclusions called Lewy bodies found in PD and cortical Lewy body dementia (LBD) were discovered to be predominantly alpha-synuclein. Aberrant aggregation of alpha-synuclein has been detected in an increasing number of neurodegenerative diseases, collectively known as synucleopathies. Alpha-synuclein exists physiologically in both soluble and membrane-bound states, in unstructured and alpha-helical conformations, respectively. The physiological function of alpha-synuclein appears to require its translocation between these subcellular compartments and interconversion between the 2 conformations. Abnormal processing of alpha-synuclein is predicted to lead to pathological changes in its binding properties and function. In this review, genetic and environmental risk factors for alpha-synuclein pathology are described. Various mechanisms for in vitro and in vivo alpha-synuclein aggregation and neurotoxicity are summarized, and their relevance to neuropathology is explored.
Bennett
M Catherine
MC
Blanchette Rockefeller Neurosciences Institute, Rockville, MD, USA. cbennett@brni-jhu.org
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009419:Nerve Tissue Proteins / Q000302:isolation & purification / Q000502:physiology / Q000633:toxicity; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism; D051381:Rats; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein