Dysregulated cholesterol drives neurodegeneration in Parkinson's disease

ABCA1 is identified as a central driver of Parkinson’s disease neurodegeneration through dysregulated cholesterol trafficking. ABCA1 expression is increased in the substantia nigra of human Parkinson’s brains and in mouse PD models, with preferential changes in nigral and striatal circuits. Elevated astrocytic ABCA1 causes excessive cholesterol efflux, which paradoxically overloads adjacent neurons. In neurons, ABCA1 concentrates on lysosomes and promotes cholesterol import into lysosomal compartments, producing lysosomal cholesterol accumulation, impaired autophagy, and accumulation of aggregated α‑synuclein. Genetic knockdown of Abca1 in astrocytes or dopaminergic neurons reduces neuronal loss and behavioral deficits in vivo, demonstrating cell-type-specific protection.

Mechanistically, lysosomal cholesterol accumulation triggered by ABCA1 activates a lysosomal cholesterol sensor (GPR155) and blocks autophagic clearance, linking cholesterol trafficking to α‑synuclein pathology and neurodegeneration. Pharmacological inhibition of ABCA1 activity with magnesium citrate lowers dopaminergic neuron loss in a preformed fibril mouse model, supporting ABCA1 inhibition as a disease‑modifying strategy distinct from cholesterol synthesis blockade. Findings span human tissues, cellular models and genetic and pharmacological interventions in mice, and position ABCA1-dependent intercellular cholesterol flow and lysosomal import as actionable targets for Parkinson’s therapy.