FIGURE 7.

Model for development of α-synuclein-mediated cytotoxicity. Proaggregatory factors such as p25α nucleate monomeric α-syn and thereby convert the monomers into better substrates for Ser-129-reactive kinases. The Ser-129 phosphorylation increases the nucleating activity of the α-syn aggregates, which favors the formation of cytotoxic Ser(P)-129 oligomers. These oligomers subsequently affect vital cellular signaling pathways that ultimately initiate slow activation of caspase-3 and its downstream prodegenerative effects comprising early MT dysfunction and subsequent apoptosis.