The chaperone Clusterin participates in α-Synuclein neuropathology in Parkinson’s disease brain

Abstract α-Synuclein aggregation and propagation are central pathogenic events in Parkinson’s disease, yet the contribution of molecular chaperones to these processes remains poorly understood. Clusterin, also known as Apolipoprotein J, is a major chaperone implicated in proteostasis and neurodegeneration and has been extensively investigated in Alzheimer’s disease but remains largely unexplored in Parkinson’s disease. In the present cross-sectional study, we aimed to investigate Clusterin distribution and its interplay with α-Synuclein pathology in the midbrain of post-mortem human brains from Parkinson’s disease patients, using complementary biochemical and neuropathological approaches. We found increased levels of secreted Clusterin in the substantia nigra of Parkinson’s disease patients accompanied by impaired microglial Clusterin internalization and clearance. Notably, analyzing Clusterin interplay with α-Synuclein pathology, we revealed a positive correlation between Clusterin levels and α-Synuclein aggregation in Parkinson’s disease and found that both proteins co-localized within pathological inclusions, including Lewy bodies, supporting a close association between Clusterin and α-Synuclein pathology. These findings support a model in which Clusterin may initially act as a protective chaperone response to misfolded α-Synuclein but becomes progressively trapped within Lewy bodies as pathology advances. Together, our results uncover the association between Clusterin dysregulation and α-Synuclein neuropathology and identify Clusterin as a potential mediator of proteostasis failure and a candidate therapeutic target in Parkinson’s disease.