Gaeta Anthony L, Willicott Karolina, Willicott Corey W, McKay Luke E, Keogh Candice M, Altman Tyler J, Kimble Logan C, Yarbrough Abigail L, Caldwell Kim A, Caldwell Guy A
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
Center for Convergent Bioscience and Medicine, The University of Alabama, Tuscaloosa, AL 35487, USA.
iScience. 2023 May 12;26(6):106859. doi: 10.1016/j.isci.2023.106859. eCollection 2023 Jun 16.
Failure of inherently protective cellular processes and misfolded protein-associated stress contribute to the progressive loss of dopamine (DA) neurons characteristic of Parkinson's disease (PD). A disease-modifying role for the microbiome has recently emerged in PD, representing an impetus to employ the soil-dwelling nematode, as a preclinical model to correlate changes in gene expression with neurodegeneration in transgenic animals grown on distinct bacterial food sources. Even under tightly controlled conditions, hundreds of differentially expressed genes and a robust neuroprotective response were discerned between clonal strains overexpressing human alpha-synuclein in the DA neurons fed either one of only two subspecies of . Moreover, this neuroprotection persisted in a transgenerational manner. Genetic analysis revealed a requirement for the double-stranded RNA (dsRNA)-mediated gene silencing machinery in conferring neuroprotection. In delineating the contribution of individual genes, evidence emerged for endopeptidase activity and heme-associated pathway(s) as mechanistic components for modulating dopaminergic neuroprotection.
帕金森病（PD）的特征是多巴胺（DA）神经元逐渐丧失，这是由内在保护性细胞过程的失败和错误折叠蛋白相关的应激反应导致的。微生物群在帕金森病中发挥疾病修饰作用的观点最近出现，这促使人们将土壤线虫作为临床前模型，以关联在不同细菌食物来源上生长的转基因动物中基因表达变化与神经退行性变之间的关系。即使在严格控制的条件下，在仅以两种亚种之一为食的多巴胺能神经元中过表达人α-突触核蛋白的克隆菌株之间，也发现了数百个差异表达基因和强烈的神经保护反应。此外，这种神经保护作用以跨代方式持续存在。遗传分析表明，双链RNA（dsRNA）介导的基因沉默机制对于赋予神经保护作用是必需的。在确定单个基因的作用时，有证据表明内肽酶活性和血红素相关途径是调节多巴胺能神经保护作用的机制组成部分。
