The role of α-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 α-synuclein protein was the first discovery linking this protein to a rare familial form of Parkinson's disease (PD). Subsequently, other mutations in the α-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 α-synuclein. Aberrant aggregation of α-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 α-helical conformations, respectively. The physiological function of α-synuclein appears to require its translocation between these subcellular compartments and interconversion between the 2 conformations. Abnormal processing of α-synuclein is predicted to lead to pathological changes in its binding properties and function. In this review, genetic and environmental risk factors for α-synuclein pathology are described. Various mechanisms for in vitro and in vivo α-synuclein aggregation and neurotoxicity are summarized, and their relevance to neuropathology is explored.