Polyglutamine diseases
Polyglutamine diseases
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DOI：
10.1016/j.conb.2021.07.001
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发表时间：
2022-02-01
影响因子：
5.7
通讯作者：
Tabrizi, Sarah J.
中科院分区：
文献类型：
--
作者：
Bunting, Emma L.;Hamilton, Joseph;Tabrizi, Sarah J.
多聚谷氨酰胺疾病是九种CAG三核苷酸扩增疾病的集合，呈现出一系列神经和临床表型。最近对亨廷顿舞蹈病的人类、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增中的作用，改变了疾病的发病机制。HTT基因的不完全剪接也被证明发生在人类身上，由此产生的外显子1片段最有可能导致亨廷顿病的表型。在脊髓小脑共济失调中，研究集中于离子通道转录失调作为关键的疾病调节剂。此外，通过转录后和翻译修饰以及自噬机制，在了解脊髓小脑共济失调中毒性、聚谷氨酰胺扩展蛋白水平增加的机制方面也取得了进展。最近对脊髓和球性肌萎缩的研究表明，类似的致病途径与更常见的多谷氨酰胺疾病有关，强调自噬刺激是一种潜在的治疗靶点。最后，反义寡核苷酸在几种多聚谷氨酰胺疾病中的治疗用途已显示出临床前益处，并可作为人类潜在的未来治疗方法。
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.