27‐Hydroxycholesterol Drives the Spread of α‐Synuclein Pathology in Parkinson's Disease

Abstract Background The accumulation and aggregation of α‐synuclein (α‐Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27‐hydroxycholesterol (27‐OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27‐OHC plays a role in α‐Syn aggregation and propagation remains elusive. Objective The aim of this study was to determine whether 27‐OHC regulates α‐Syn aggregation and propagation. Methods Purified recombinant α‐Syn, neuronal cultures, and α‐Syn fibril‐injected mouse model of PD were treated with 27‐OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27‐OHC on α‐Syn pathology in vivo. Results 27‐OHC accelerates the aggregation of α‐Syn and enhances the seeding activity of α‐Syn fibrils. Furthermore, the 27‐OHC‐modified α‐Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27‐OHC‐modified α‐Syn fibrils induces enhanced spread of α‐Syn pathology and dopaminergic neurodegeneration compared with pure α‐Syn fibrils. Similarly, subcutaneous administration of 27‐OHC facilitates the seeding of α‐Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27‐OHC, ameliorates the spread of pathologic α‐Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27‐OHC plays an important role in the pathogenesis of PD. Conclusions 27‐OHC promotes the aggregation and spread of α‐Syn. Strategies aimed at inhibiting the CYP27A1‐27‐OHC axis may hold promise as a disease‐modifying therapy to halt the progression of α‐Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.