Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Neurobiol Dis. 2022 Jul;169:105721. doi: 10.1016/j.nbd.2022.105721. Epub 2022 Apr 8.
In recent years progress in molecular biology and genetics have advanced our understanding of neurological disorders and highlighted synergistic relationships with inflammatory and age-related processes. Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Increasing extensive evidence supports the contribution of genetic risk variants and inflammation in the pathobiology of this disease. Functional and genetic studies demonstrate an overlap between genes linked to increased risk for PD and autoimmune diseases. Variants identified in loci adjacent to LRRK2, GBA, and HLA establish a crosstalk between the pathobiologies of the two disease spectra. Furthermore, common signalling pathways associated with the pathogenesis of genetic PD are also relevant to inflammatory signaling include MAPK, NF-κB, Wnt and inflammasome signaling. Importantly, post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines. In this review we will focus on the principal mechanisms of genetic, inflammatory and age-related risk that intersect in the pathogenesis of PD.
近年来，分子生物学和遗传学的进展提高了我们对神经紊乱的理解，并强调了它们与炎症和与年龄相关的过程的协同关系。帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质致密部（SNpc）中的多巴胺能神经元丧失。越来越多的证据支持遗传风险变异和炎症在这种疾病的发病机制中的作用。功能和遗传研究表明，与 PD 和自身免疫性疾病风险增加相关的基因之间存在重叠。在 LRRK2、GBA 和 HLA 附近位置鉴定出的变异建立了两种疾病谱的发病机制之间的串扰。此外，与遗传 PD 的发病机制相关的常见信号通路也与炎症信号有关，包括 MAPK、NF-κB、Wnt 和炎性小体信号。重要的是，PD 患者的大脑和脑脊液的死后分析显示促炎细胞因子的积累。在这篇综述中，我们将重点讨论在 PD 发病机制中相互交叉的遗传、炎症和与年龄相关的主要风险机制。
