Abstract
<title>Abstract</title> <p> 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 <italic>post-mortem</italic> human brains from Parkinson’s disease patients, using complementary biochemical and neuropathological approaches. We found increased levels of secreted Clusterin in the <italic>substantia nigra</italic> 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. </p>