ABCA1 Cholesterol Transporter Identified as Key Driver of Parkinson’s Neurodegeneration
A new study in Nature Neuroscience identifies the ATP-binding cassette transporter A1 (ABCA1) as a critical regulator of cholesterol homeostasis in Parkinson’s disease (PD). Researchers found that ABCA1 expression is elevated in the substantia nigra of postmortem PD brains and mouse models. This elevation drives excessive cholesterol efflux from astrocytes, leading to cholesterol overload in neurons. In neurons, ABCA1 localizes to lysosomes, facilitating cholesterol import that causes accumulation, autophagy impairment, and alpha-synuclein pathology. Genetic silencing of ABCA1 in astrocytes or dopaminergic neurons reduced neurodegeneration and behavioral deficits in mice. Additionally, magnesium citrate, identified as an ABCA1 inhibitor, reduced dopaminergic neuronal loss in PD mouse models, suggesting ABCA1 inhibition as a potential disease-modifying strategy.