脊髓小脑共济失调是一组表型和遗传异质性的常染色体显性遗传性退行性疾病。基因突变谱包括动态扩展,点突变,重复,插入,和不同长度的删除。动态扩展是最常见的突变形式。突变通常会导致无法区分的临床表型,因此需要使用多种基因检测技术进行验证。根据突变的类型,发病机制可能涉及蛋白质毒性,RNA毒性,或蛋白质功能丧失。所有这些都可能破坏一系列的细胞过程,如受损的蛋白质质量控制途径,离子通道功能障碍,线粒体功能障碍,转录失调,DNA损伤,核完整性的丧失,最终,导致疾病的神经元功能和完整性的损害。许多疾病改善疗法,比如基因编辑技术,RNA干扰,反义寡核苷酸,干细胞技术,药物疗法目前正在临床试验中。然而,治疗遗传疾病的方法的发展仍然是一个全球性的挑战,被技术所困扰,伦理,和其他挑战。因此,脊髓小脑性共济失调发病机制的研究对于疾病修饰分子疗法的持续发展具有重要意义。
Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.