Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations

Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the alpha-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes alpha-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of alpha-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of alpha-synuclein toxicity. We critically assess the potential of experimental therapies targeting alpha-synuclein, and discuss steps that need to be taken for target validation and drug development.