Dysregulated cholesterol trafficking through ABCA1 drives neurodegeneration in Parkinson's disease.

Abstract

Although brain cholesterol dysregulation is implicated in Parkinson's disease (PD), targeting cholesterol synthesis has shown limited efficacy. Here we identify ATP-binding cassette transporter A1 (ABCA1) as a critical regulator of cholesterol homeostasis in PD. We show that ABCA1 expression is elevated in the substantia nigra of postmortem PD brains and in a PD mouse model, with regional analyses revealing preferential alterations in nigral and striatal circuits. Mechanistically, astrocytic ABCA1 drives excessive cholesterol efflux in mice, promoting neuronal cholesterol overload. In neurons, ABCA1 localizes to lysosomes, where it facilitates cholesterol import, leading to cholesterol accumulation, autophagy impairment and α-synuclein pathology. Genetic silencing of Abca1 in either astrocytes or dopaminergic neurons attenuates neurodegeneration and behavioral deficits in vivo. Furthermore, we identify magnesium citrate as an ABCA1 inhibitor and show that it reduces dopaminergic neuronal loss in a PD mouse model. Our findings identify an ABCA1-dependent cholesterol pathway underlying PD pathogenesis and support ABCA1 inhibition as a potential disease-modifying strategy.