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

Background: The accumulation and aggregation of alpha-synuclein (alpha-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 alpha-Syn aggregation and propagation remains elusive. Objective: The aim of this study was to determine whether 27-OHC regulates alpha-Syn aggregation and propagation. Methods: Purified recombinant alpha-Syn, neuronal cultures, and alpha-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 alpha-Syn pathology in vivo. Results: 27-OHC accelerates the aggregation of alpha-Syn and enhances the seeding activity of alpha-Syn fibrils. Furthermore, the 27-OHC-modified alpha-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified alpha-Syn fibrils induces enhanced spread of alpha-Syn pathology and dopaminergic neurodegeneration compared with pure alpha-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of alpha-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic alpha-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 alpha-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a diseasemodifying therapy to halt the progression of alpha-Syn pathology in PD. (c) 2023 International Parkinson and Movement Disorder Society.