UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK; UK Dementia Research Institute, University College London, London, WC1N 3BG, UK.
Curr Opin Neurobiol. 2022 Feb;72:39-47. doi: 10.1016/j.conb.2021.07.001. Epub 2021 Sep 3.
Polyglutamine diseases are a collection of nine CAG trinucleotide expansion disorders, presenting with a spectrum of neurological and clinical phenotypes. Recent human, mouse and cell studies of Huntington's disease have highlighted the role of DNA repair genes in somatic expansion of the CAG repeat region, modifying disease pathogenesis. Incomplete splicing of the HTT gene has also been shown to occur in humans, with the resulting exon 1 fragment most probably contributing to the Huntington's disease phenotype. In the spinocerebellar ataxias, studies have converged on transcriptional dysregulation of ion channels as a key disease modifier. In addition, advances have been made in understanding how increased levels of toxic, polyglutamine-expanded proteins can arise in the spinocerebellar ataxias through post-transcriptional and -translational modifications and autophagic mechanisms. Recent studies in spinal and bulbar muscular atrophy implicate similar pathogenic pathways to the more common polyglutamine diseases, highlighting autophagy stimulation as a potential therapeutic target. Finally, the therapeutic use of antisense oligonucleotides in several polyglutamine diseases has shown preclinical benefits and serves as potential future therapies in humans.
多聚谷氨酰胺疾病是由九个 CAG 三核苷酸扩展紊乱组成的一类疾病，表现出一系列神经和临床表型。最近对亨廷顿病的人类、小鼠和细胞研究强调了 DNA 修复基因在 CAG 重复区域的体细胞扩展中的作用，从而改变了疾病的发病机制。在人类中也已经显示出 HTT 基因的不完全剪接，产生的外显子 1 片段很可能导致亨廷顿病表型。在脊髓小脑共济失调中，研究集中在离子通道转录失调作为关键疾病修饰因子上。此外，人们在理解如何通过转录后和翻译后修饰以及自噬机制，使毒性、多聚谷氨酰胺扩展蛋白在脊髓小脑共济失调中增加方面取得了进展。最近对脊髓延髓肌萎缩症的研究表明，类似的致病途径与更常见的多聚谷氨酰胺疾病有关，强调自噬刺激作为一种潜在的治疗靶点。最后，在几种多聚谷氨酰胺疾病中使用反义寡核苷酸的治疗已显示出临床前益处，并可能成为人类未来的治疗方法。
