Fig. 3.

Mediators of α-syn pathology. a α-Syn aggregation is promoted by various genetic mutations (i.e., the A53T SNCA mutation) or increased cytosolic concentration via whole-gene SNCA duplication and triplication. b Aggregated α-syn species, as well as deficient activity of a number of lysosomal synucleinopathy risk factors (i.e., variants in the ATP13A2, GBA or CTSD genes), can interfere with autophagic/lysosomal function resulting in increased aggregation of α-syn. c Lysosomal impairment can directly or indirectly affect mitochondrial health and function, which may ultimately mediate toxicity in synucleinopathies; release of α-syn seeds upon cell death or as a regulated function of cell stress may initiate the transmission of individual α-syn seeds. Cell-to-cell transmission of pathological α-syn in diverse synucleinopathies could be mediated via imbalances in any of these processes