Lipids: Key Players That Modulate α-Synuclein Toxicity and Neurodegeneration in Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease; it is characterized by the loss of dopaminergic neurons in the midbrain and the accumulation of neuronal inclusions, mainly consisting of alpha-synuclein (alpha-syn) fibrils in the affected regions. The prion-like property of the pathological forms of alpha-syn transmitted via neuronal circuits has been considered inherent in the nature of PD. Thus, one of the potential targets in terms of PD prevention is the suppression of alpha-syn conversion from the functional form to pathological forms. Recent studies suggested that alpha-syn interacts with synaptic vesicle membranes and modulate the synaptic functions. A series of studies suggest that transient interaction of alpha-syn as multimers with synaptic vesicle membranes composed of phospholipids and other lipids is required for its physiological function, while an alpha-syn-lipid interaction imbalance is believed to cause alpha-syn aggregation and the resultant pathological alpha-syn conversion. Altered lipid metabolisms have also been implicated in the modulation of PD pathogenesis. This review focuses on the current literature reporting the role of lipids, especially phospholipids, and lipid metabolism in alpha-syn dynamics and aggregation processes.