Alterations in the SH-SY5Y cell transcriptome induced by cholesterol treatment

We establish that PD-associated hyperactivity of astrocytic ABCA1 drives excessive cholesterol efflux, inducing neuronal cholesterol overload and injury. This overload amplifies ABCA1 specifically within neuronal lysosomes, facilitating pathological cholesterol import. Subsequent lysosomal cholesterol accumulation activates GPR155 signaling to initiate mTOR-mediated autophagy suppression, culminating in α-Synuclein aggregation and neurodegeneration.

Conditional knockdown of Abca1 in dopaminergic neurons mitigates α-Synuclein pathology and neurodegeneration in vivo. Furthermore, molecular docking identifies magnesium citrate, an FDA-approved laxative, as a potent ABCA1 inhibitor. Magnesium citrate administration enhances dopaminergic neuronal survival dose-dependently in PD mice.

Collectively, our findings delineate a novel ABCA1-regulated pathway driving PD pathogenesis, providing compelling genetic and pharmacological proof-of-concept supporting ABCA1 inhibition as a promising disease-modifying strategy for PD.