Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.
Int J Mol Sci. 2021 Jan 18;22(2):914. doi: 10.3390/ijms22020914.
Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model. Drugs were identified that had both positive and negative effects on cell phenotypes. To the best of our knowledge, this study is the first report of the Golgi apparatus playing a role in the pathology of CMT disorders. The drugs we identified, using our yeast-based CMT-GDAP1 model, may be further used in translational research.
腓骨肌萎缩症（CMT）是一种遗传性神经退行性疾病，具有很大的遗传异质性。通过分子遗传学，已经广泛地对导致这种异质性的基因和突变进行了描述。然而，绝大多数 CMT 亚型的分子发病机制仍然是未知的。由于缺乏对分子水平发病机制的了解，任何对 CMT 疾病进行实验性治疗的尝试都受到限制。在这项研究中，我们旨在使用酵母和人类细胞的基于模型的 CMT-GDAP1 疾病，鉴定由编码 GDAP1 的基因突变引起的分子途径的紊乱。我们发现，导致 GDAP1 蛋白表达减少的一些突变导致高尔基体的选择性破坏。这些结构改变伴随着高尔基体内部的功能紊乱。我们使用基于酵母的 CMT-GDAP1 模型筛选了市场上可获得的 1500 多种药物。发现了一些对细胞表型既有积极影响又有消极影响的药物。据我们所知，这项研究首次报道了高尔基体在 CMT 疾病病理中的作用。我们使用基于酵母的 CMT-GDAP1 模型鉴定的药物可能会进一步用于转化研究。
