A personalised and comprehensive approach is required to suppress or replenish SNCA for Parkinson's disease

Based on the prevailing α-synuclein "gain-of-function" hypothesis, reducing α-synuclein levels and removing its aggregates is a current focus of disease-modifying therapies for Parkinson's disease. Emerging evidence of α-synuclein "loss-of-function" suggests that it may be necessary to replenish monomeric α-synuclein levels. We propose a personalized and comprehensive approach for different Parkinson's subgroups based on whether α-synuclein is likely to contribute to disease pathogenesis through a "gain-of-function", "loss-of-function", or both mechanisms.