α-Synuclein Activates the PI3K/AKT Pathway to Drive Lipid Droplets Accumulation: Implications for Parkinson's Disease

Growing evidence supports a metabolic component in Parkinson's disease (PD). alpha-Synuclein (aSyn), a protein central to the onset and progression of PD, facilitates the accumulation of neuronal lipid droplets, which are implicated in disease pathology. We report that AKT is hyper-phosphorylated in PD brains and show that aSyn enhances p110α activity by facilitating palmitoylated Ras localization to the plasma membrane, driving lipid droplet accumulation through PI3K/AKT/mTOR and PPARγ activation. Phosphorylation of aSyn at Ser129 correlates positively with the localization of Ras to the membrane fraction and with accumulation of lipid droplets. In-vivo treatment of young, asymptomatic aSynA53T transgenic mice with GDC-0084 (paxalisib), a blood-brain barrier-permeable PI3K inhibitor, restored healthy AKT activity levels, reduced levels of PSer129 and aSyn oligomers, decreased neuronal lipid droplet accumulation, and promoted lysosomal clustering. These findings establish a role for aSyn in p110a activation during early, asymptomatic stages of the disease and highlight the therapeutic potential of PI3K inhibition as a disease-modifying strategy.