ABC-RI, Algarve Biomedical Center Research Institute, Faro, Portugal.
Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Faro, Portugal.
J Neurochem. 2024 Aug;168(8):1442-1459. doi: 10.1111/jnc.16010. Epub 2023 Nov 22.
Polyglutamine spinocerebellar ataxias (PolyQ SCAs) represent a group of monogenetic diseases in which the expanded polyglutamine repeats give rise to a mutated protein. The abnormally expanded polyglutamine protein produces aggregates and toxic species, causing neuronal dysfunction and neuronal death. The main symptoms of these disorders include progressive ataxia, motor dysfunction, oculomotor impairment, and swallowing problems. Nowadays, the current treatments are restricted to symptomatic alleviation, and no existing therapeutic strategies can reduce or stop the disease progression. Even though the origin of these disorders has been associated with polyglutamine-induced toxicity, RNA toxicity has recently gained relevance in polyQ SCAs molecular pathogenesis. Therefore, the research's focus on RNA metabolism has been increasing, especially on RNA-binding proteins (RBPs). The present review summarizes RNA metabolism, exposing the different processes and the main RBPs involved. We also explore the mechanisms by which RBPs are dysregulated in PolyQ SCAs. Finally, possible therapies targeting the RNA metabolism are presented as strategies to reverse neuropathological anomalies and mitigate physical symptoms.
多聚谷氨酰胺小脑共济失调（PolyQ SCAs）是一组单基因疾病，其中扩增的多聚谷氨酰胺重复序列导致突变蛋白的产生。异常扩增的多聚谷氨酰胺蛋白产生聚集物和毒性物质，导致神经元功能障碍和神经元死亡。这些疾病的主要症状包括进行性共济失调、运动功能障碍、眼球运动障碍和吞咽问题。目前，这些疾病的治疗方法仅限于症状缓解，没有现有的治疗策略可以减少或阻止疾病的进展。尽管这些疾病的起源与多聚谷氨酰胺诱导的毒性有关，但 RNA 毒性最近在 PolyQ SCAs 的分子发病机制中得到了重视。因此，研究人员越来越关注 RNA 代谢，特别是 RNA 结合蛋白（RBPs）。本文综述了 RNA 代谢，阐述了不同的过程和涉及的主要 RBPs。我们还探讨了 RBPs 在 PolyQ SCAs 中失调的机制。最后，提出了针对 RNA 代谢的可能治疗方法，作为逆转神经病理学异常和减轻身体症状的策略。
