Challenges and complexities of α-synuclein toxicity: New postulates in unfolding the mystery associated with Parkinson's disease

The discovery of two missense mutations in α-synuclein gene and the identification of the α-synuclein as the major component of Lewy bodies and Lewy neurites have imparted a new direction in understanding Parkinson's disease. Now that α-synuclein has been implicated in several neurodegenerative disorders makes it increasingly clear that aggregation of α-synuclein is a hallmark feature in neurodegeneration. Although little has been learned about its normal function, α-synuclein appears to be associated with membrane phospholipids and may therefore participate in a number of cell signaling pathways. Here, we review the localization, structure, and function of α-synuclein and provide a new hypothesis on, (a) the disruption in the membrane binding ability of synuclein which may be the major culprit leading to the α-synuclein aggregation and (b) the complexity associated with nuclear localization of α-synuclein and its possible binding property to DNA. Further, we postulated the three possible mechanisms of synuclein induced neuronal degeneration in Parkinson's disease.