The cholesterol 24-hydroxylase enzyme, CYP46A1, reduces overexpressed alpha-synuclein proteins in human cellular models of Parkinson’s disease.

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Abstract A growing body of evidence suggests a correlation between cholesterol metabolism and the pathogenesis of Parkinson's disease (PD). We and others have demonstrated that the activation of the cholesterol 24-hydroxylase enzyme, CYP46A1, responsible for converting cholesterol to 24S-hydroxycholesterol (24-OHC) in the brain, is an effective therapeutic strategy for several neurodegenerative diseases as Alzheimer's disease, Huntington’s disease, spinocerebellar ataxia type 3. This approach has demonstrated that overexpression of CYP46A1 can reduce aggregated protein levels, enhance memory and cognitive performance, and improve motor phenotype in animal models. Nevertheless, there is still much to be illuminated regarding the role of CYP46A1 in PD. Alpha-synuclein (alpha-syn), the hallmark pathological protein of PD, exhibits a pronounced affinity for binding to lipid membranes, especially in cholesterol-rich regions and contains a high-affinity cholesterol-binding motif in the 67–78 aa region. In this study, we demonstrate that overexpression of human CYP46A1 leads to a decreased expression of wild-type alpha-syn proteins in human neuroblastoma SH-SY5Y cells through the autophagy-lysosomal pathway. Additionally, our findings suggest that CYP46A1 may also decrease the levels of alpha-syn proteins overexpressed with mutations in the cholesterol-binding domain or at the residue A53T, which is associated with familial pathology. Moreover, CYP46A1 retains its functionality in a cellular model of PD associated with GBA1. The gene GBA1 is involved in lipid metabolism, and its deficiency represents the most prevalent genetic factor associated with an elevated risk of PD. These results provide insights into disease pathogenesis and potential therapeutic pathways that could benefit patients with PD.

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