Abstract

Dozens of incurable neurological disorders result from expansion of short repeat sequences in both coding and non-coding regions of the transcriptome. Short repeat expansions underlie microsatellite repeat expansion (MRE) disorders including myotonic dystrophy (DM1, CUG_50-3,500 in DMPK; DM2, CCTG_75-11,000 in ZNF9), fragile X tremor ataxia syndrome (FXTAS, CGG_50-200 in FMR1), spinal bulbar muscular atrophy (SBMA, CAG_40-55 in AR), Huntington’s disease (HD, CAG_36-121 in HTT), C9ORF72- amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD and C9-ALS/FTD, GGGGCC in C9ORF72), and many others, like ataxias. Recent research has highlighted several mechanisms that may contribute to pathology in this heterogeneous class of neurological MRE disorders – bidirectional transcription, intranuclear RNA foci, and repeat associated non-AUG (RAN) translation – which are the subject of this review. Additionally, many MRE disorders share similar underlying molecular pathologies that have been recently targeted in experimental and preclinical contexts. We discuss the therapeutic potential of versatile therapeutic strategies that may selectively target disrupted RNA-based processes and may be readily adaptable for the treatment of multiple MRE disorders. Collectively, the strategies under consideration for treatment of multiple MRE disorders include reducing levels of toxic RNA, preventing RNA foci formation, and eliminating the downstream cellular toxicity associated with peptide repeats produced by RAN translation. While treatments are still lacking for the majority of MRE disorders, several promising therapeutic strategies have emerged and will be evaluated within this review.

摘要

数十种无法治愈的神经系统疾病是由转录组编码区和非编码区中短重复序列的扩展引起的。短重复扩张背后微卫星重复序列扩张（MRE）病症，包括强直性肌营养不良（DM1，CUG _50-3,500在DMPK ; DM2，CCTG _75-11,000中ZNF9），脆性X震颤共济失调综合征（FXTAS，CGG _50-200在FMR1），脊髓延髓肌萎缩症（SBMA，AR 中的CAG _40-55），亨廷顿病（HD，CAG _36-121）在 HTT 中），C9ORF72-肌萎缩侧索硬化（ALS）/额颞叶痴呆（FTD 和 C9-ALS/FTD，C9ORF72 中的 GGGGCC），以及许多其他疾病，如共济失调。最近的研究强调了几种可能导致此类异质神经 MRE 疾病病理学的机制——双向转录、核内 RNA 病灶和重复相关的非 AUG (RAN) 翻译——这是本综述的主题。此外，许多 MRE 疾病具有相似的潜在分子病理学，这些病理学最近已在实验和临床前环境中成为目标。我们讨论了多种治疗策略的治疗潜力，这些策略可以选择性地针对破坏的基于 RNA 的过程，并且可以很容易地适应多种 MRE 疾病的治疗。总的来说，正在考虑治疗多种 MRE 疾病的策略包括降低有毒 RNA 的水平，防止 RNA 病灶形成，以及消除与 RAN 翻译产生的肽重复相关的下游细胞毒性。虽然大多数 MRE 疾病仍然缺乏治疗方法，但已经出现了几种有希望的治疗策略，并将在本次审查中进行评估。