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α-Synuclein-dependent Increases in PIP5K1γ Drive Inositol Signaling to Promote Neurotoxicity

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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.

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This item is under embargo until February 14, 2024.