Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
Int J Mol Sci. 2020 Jun 16;21(12):4282. doi: 10.3390/ijms21124282.
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by the loss of motor control and cognitive ability, which eventually leads to death. The mutant huntingtin protein (HTT) exhibits an expansion of a polyglutamine repeat. The mechanism of pathogenesis is still not fully characterized; however, evidence suggests that post-translational modifications (PTMs) of HTT and upstream and downstream proteins of neuronal signaling pathways are involved. The determination and characterization of PTMs are essential to understand the mechanisms at work in HD, to define possible therapeutic targets better, and to challenge the scientific community to develop new approaches and methods. The discovery and characterization of a panoply of PTMs in HTT aggregation and cellular events in HD will bring us closer to understanding how the expression of mutant polyglutamine-containing HTT affects cellular homeostasis that leads to the perturbation of cell functions, neurotoxicity, and finally, cell death. Hence, here we review the current knowledge on recently identified PTMs of HD-related proteins and their pathophysiological relevance in the formation of abnormal protein aggregates, proteolytic dysfunction, and alterations of mitochondrial and metabolic pathways, neuroinflammatory regulation, excitotoxicity, and abnormal regulation of gene expression.
亨廷顿舞蹈症（HD）是一种常染色体显性遗传的神经退行性疾病，其特征为运动控制和认知能力丧失，最终导致死亡。突变的亨廷顿蛋白（HTT）表现出多聚谷氨酰胺重复序列的扩增。发病机制尚未完全明确；然而，有证据表明HTT的翻译后修饰（PTM）以及神经信号通路的上下游蛋白都参与其中。PTM的确定和表征对于理解HD的发病机制、更好地定义可能的治疗靶点以及促使科学界开发新的方法至关重要。在HTT聚集和HD细胞事件中发现并表征一系列PTM，将使我们更接近了解含多聚谷氨酰胺突变的HTT表达如何影响细胞稳态，进而导致细胞功能紊乱、神经毒性并最终导致细胞死亡。因此，在此我们综述了目前关于HD相关蛋白最近鉴定出的PTM及其在异常蛋白聚集体形成、蛋白水解功能障碍、线粒体和代谢途径改变、神经炎症调节、兴奋性毒性以及基因表达异常调节中的病理生理相关性的知识。
