GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE303nnn/GSE303508/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303508GEOGSEfalseAlterations in the SH-SY5Y cell transcriptome induced by cholesterol treatmentParkinson’s disease (PD) is a progressive neurodegenerative disorder lacking disease-modifying therapies. Brain cholesterol dysregulation constitutes a recognized pathogenic mechanism, yet therapeutic inhibition of cholesterol synthesis has proven ineffective or detrimental. Here, we identify ATP-binding cassette transporter A1 (ABCA1) as a pivotal regulator of brain cholesterol homeostasis in PD. Dysregulated cholesterol metabolism and elevated ABCA1 expression occur in the substantia nigra of post-mortem PD patients and established PD models. Crucially, normal human brain tissue exhibits high basal ABCA1 expression in PD-vulnerable regions, underscoring its physiological relevance. Single-cell transcriptomics reveals predominant Abca1 expression in murine substantia nigra astrocytes and dopaminergic neurons. 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.2026/08/27GSE303508GSM9128245GSM9128246GSM9128247GSM9128248GSM9128250GSM912824924676303508Homo sapiens