Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Mov Disord. 2023 Nov;38(11):2005-2018. doi: 10.1002/mds.29577. Epub 2023 Aug 18.
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.
The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation.
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.
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.
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.
α-突触核蛋白（α-Syn）的积累和聚集是帕金森病（PD）的特征。流行病学证据表明，高血脂与 PD 风险增加有关。胆固醇氧化产物 27-羟胆固醇（27-OHC）的水平在 PD 患者的大脑和脑脊液中增加。然而，27-OHC 是否在 α-Syn 聚集和传播中发挥作用仍不清楚。
本研究旨在确定 27-OHC 是否调节 α-Syn 的聚集和传播。
用 27-OHC 处理纯化的重组 α-Syn、神经元培养物和α-Syn 纤维注射的 PD 小鼠模型。此外，还使用 CYP27A1 基因敲除小鼠来研究体内降低 27-OHC 对 α-Syn 病理学的影响。
27-OHC 加速了 α-Syn 的聚集并增强了 α-Syn 纤维的种子活性。此外，27-OHC 修饰的 α-Syn 纤维定位于线粒体并诱导线粒体功能障碍和神经毒性。与纯 α-Syn 纤维相比，注射 27-OHC 修饰的 α-Syn 纤维可诱导 α-Syn 病理学的增强传播和多巴胺能神经退行性变。同样，皮下给予 27-OHC 可促进 α-Syn 病理学的播种。胆固醇 27-羟化酶（CYP27A1）的基因缺失（该酶将胆固醇转化为 27-OHC）可改善病理性 α-Syn 的传播、黑质纹状体多巴胺能通路的退化和运动障碍。这些结果表明胆固醇代谢产物 27-OHC 在 PD 的发病机制中起重要作用。
27-OHC 促进 α-Syn 的聚集和传播。抑制 CYP27A1-27-OHC 轴的策略可能有希望成为一种疾病修饰疗法，以阻止 PD 中 α-Syn 病理学的进展。
