Minakawa Eiko N, Nagai Yoshitaka
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Front Neurosci. 2021 Feb 12;15:621996. doi: 10.3389/fnins.2021.621996. eCollection 2021.
The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases caused by the abnormal expansion of a CAG trinucleotide repeat that are translated into an expanded polyQ stretch in the disease-causative proteins. The expanded polyQ stretch itself plays a critical disease-causative role in the pathomechanisms underlying polyQ diseases. Notably, the expanded polyQ stretch undergoes a conformational transition from the native monomer into the β-sheet-rich monomer, followed by the formation of soluble oligomers and then insoluble aggregates with amyloid fibrillar structures. The intermediate soluble species including the β-sheet-rich monomer and oligomers exhibit substantial neurotoxicity. Therefore, protein conformation stabilization and aggregation inhibition that target the upstream of the insoluble aggregate formation would be a promising approach toward the development of disease-modifying therapies for polyQ diseases. PolyQ aggregation inhibitors of different chemical categories, such as intrabodies, peptides, and small chemical compounds, have been identified through intensive screening methods. Among them, recent advances in the brain delivery methods of several peptides and the screening of small chemical compounds have brought them closer to clinical utility. Notably, the recent discovery of arginine as a potent conformation stabilizer and aggregation inhibitor of polyQ proteins both and have paved way to the clinical trial for the patients with polyQ diseases. Meanwhile, expression reduction of expanded polyQ proteins would be another promising approach toward disease modification of polyQ diseases. Gene silencing, especially by antisense oligonucleotides (ASOs), have succeeded in reducing the expression of polyQ proteins in the animal models of various polyQ diseases by targeting the aberrant mRNA with expanded CAG repeats. Of note, some of these ASOs have recently been translated into clinical trials. Here we overview and discuss these recent advances toward the development of disease modifying therapies for polyQ diseases. We envision that combination therapies using aggregation inhibitors and gene silencing would meet the needs of the patients with polyQ diseases and their caregivers in the near future to delay or prevent the onset and progression of these currently intractable diseases.
聚谷氨酰胺（polyQ）疾病是一组遗传性神经退行性疾病，由CAG三核苷酸重复序列异常扩增引起，该重复序列在致病蛋白中被翻译成扩展的聚谷氨酰胺片段。扩展的聚谷氨酰胺片段本身在polyQ疾病的发病机制中起着关键的致病作用。值得注意的是，扩展的聚谷氨酰胺片段会经历从天然单体到富含β折叠的单体的构象转变，随后形成可溶性寡聚体，然后形成具有淀粉样纤维结构的不溶性聚集体。包括富含β折叠的单体和寡聚体在内的中间可溶性物种表现出显著的神经毒性。因此，针对不溶性聚集体形成上游的蛋白质构象稳定和聚集抑制将是开发针对polyQ疾病的疾病修饰疗法的一种有前景的方法。通过深入的筛选方法，已经鉴定出不同化学类别的polyQ聚集抑制剂，如细胞内抗体、肽和小分子化合物。其中，几种肽的脑递送方法和小分子化合物的筛选方面的最新进展使它们更接近临床应用。值得注意的是，最近发现精氨酸作为polyQ蛋白的有效构象稳定剂和聚集抑制剂，为polyQ疾病患者的临床试验铺平了道路。同时，降低扩展的聚谷氨酰胺蛋白的表达将是另一种有前景的针对polyQ疾病进行疾病修饰的方法。基因沉默，特别是通过反义寡核苷酸（ASO），已成功通过靶向具有扩展CAG重复序列的异常mRNA，在各种polyQ疾病的动物模型中降低了聚谷氨酰胺蛋白的表达。值得注意的是，其中一些ASO最近已进入临床试验。在此，我们概述并讨论了针对polyQ疾病开发疾病修饰疗法的这些最新进展。我们设想，使用聚集抑制剂和基因沉默的联合疗法将在不久的将来满足polyQ疾病患者及其护理人员的需求，以延迟或预防这些目前难以治疗的疾病的发作和进展。
