α-Synuclein Activates Ras–PI3K/AKT/mTOR Signaling to Drive Pathology in Parkinson’s Disease

<title>Abstract</title> <p> Dysregulation of the PI3K/AKT/mTOR pathway has been implicated in Parkinson’s disease (PD), yet the role of α-Synuclein (α-Syn), a protein closely associated with disease onset and progression, in modulating this pathway remains unclear. Here, we show that α-Syn enhances Ras localization to the plasma membrane to activate the PI3K/AKT/mTOR pathway, regulating neuronal lipid metabolism. We used human and α-Syn ^A53T tg mouse brains, and primary neurons to investigate the role of α-Syn's in Ras-PI3K/AKT/mTOR signaling, combining biochemical and imaging approaches to quantify and analyse neutral lipid stores and lipid droplet–lysosome dynamics. α-Syn stabilizes palmitoylated Ras at the plasma membrane, promoting Ras activation and downstream PI3K signaling. This increases neutral lipid stores, and alters their mobilization between lipid droplets and the lysosomes in response to nutrient availability and mTOR activation status. Notably, PSer129 α-Syn levels positively correlated with neuronal PI3K/AKT activity. Treatment of α-Syn ^A53T mice with the brain-penetrant PI3K inhibitor GDC-0084 (paxalisib) restored phosphorylated AKT levels, up-regulated autophagic flux, and reduced both α-Syn oligomers and pathogenic PSer129 α-Syn-positive inclusions. The inhibitor also reduced neuronal lipid accumulation and restored lipid homeostasis. These findings identify a pathogenic role for α-Syn in driving Ras–PI3K/AKT/mTOR signaling and consequent lipid-metabolism dysregulation, and support PI3K inhibition as a potential therapeutic strategy for PD. </p>