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

Growing evidence supports a metabolic component in Parkinsons disease (PD). - Synuclein (-Syn), 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 -Syn enhances p110 activity by facilitating palmitoylated Ras localization to the plasma membrane, driving lipid droplet accumulation through PI3K/AKT/mTOR and PPAR{gamma} activation. Phosphorylation of -Syn 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 -SynA53T transgenic mice with GDC-0084 (paxalisib), a blood- brain barrier-permeable PI3K inhibitor, restored healthy AKT activity levels, reduced levels of PSer129 and -Syn oligomers, decreased neuronal lipid droplet accumulation, and promoted lysosomal clustering. These findings establish a role for -Syn in p110 activation during early, asymptomatic stages of the disease and highlight the therapeutic potential of PI3K inhibition as a disease-modifying strategy. Highlight-Syn activates PI3K/AKT by promoting the localization of palmitoylated Ras to membranes, linking metabolic dysfunction to PD.