UC Davis

Anomalous aggregation of the neuronal protein α-Synuclein (α-Syn) is a pathological hallmark of Parkinson’s Disease (PD). Despite its strong link to PD and other synucleinopathies, the precise molecular mechanisms that facilitate α-Syn aggregation leading to neurodegeneration have yet to be elucidated. Here, we find that elevations in α-Syn lead to an increase in the plasma membrane (PM) phosphoinositide PI(4,5)P2, which precipitates α-Syn aggregation and drives toxic increases in mitochondrial Ca2+ and reactive oxygen species leading to neuronal death in PD. Upstream of this deleterious signaling pathway is PIP5K1γ, whose abundance and localization is enhanced at the PM by α-Syn-dependent increases in PLK1 activity. Selectively inhibiting these upstream mediators prevents α-Syn aggregation and rescues cellular phenotypes of toxicity. Collectively, this data suggest that modulation of phosphoinositide metabolism may be a therapeutic target to slow neurodegeneration in PD and other related neurodegenerative disorders.