α-Synuclein 2.0 — Moving towards Cell Type Specific Pathophysiology

Since the landmark discovery that point mutations in the α-synuclein gene (SNCA) cause familial Parkinson's disease (PD) more than 2 decades ago, extensive research has been conducted to unravel the molecular and cellular mechanisms by which α-synuclein drives PD pathogenesis resulting in selective neurodegeneration of vulnerable neuronal populations. Current interest focuses on the identification of relevant toxic α-synuclein conformers and their interaction with basic cellular functions. In this context, seminal advances have been made in defining mechanisms of α-synuclein's toxicity in neurons, but many open questions remain regarding its neuronal subtype pathophysiology, as well as the defining the most disease relevant conformations. Moreover, we still only have a partial understanding of the full spectrum of α-synuclein's physiological functions both in neurons and in other cells. In this short review, we focus on cell-specific responses to α-synuclein with a focus on the toxic conformers of α-synuclein. We will not discuss more general cellular death pathways, which have been comprehensively covered by a number of elegant recent reviews.