PDF(Pubmed)
Abstract：
Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer\'s disease, amyotrophic lateral sclerosis, Parkinson\'s disease, and Huntington\'s disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.
摘要：
脊髓小脑性共济失调3型（SCA3）是最常见的显性遗传性共济失调。目前,对于这种进行性神经退行性疾病，没有预防性或改善疾病的治疗方法，尽管使用基因沉默方法的努力正在临床试验中。该疾病是由突变基因中的CAG重复扩增引起的，ATXN3，在突变蛋白中产生扩大的聚谷氨酰胺束。与其他典型的神经退行性疾病相似，评估致病机制的研究主要集中在神经元的影响。因此,治疗性干预通常忽略非神经元对疾病的影响。我们的实验室最近报道，少突胶质细胞在SCA3小鼠中表现出一些最早和最进行性的功能障碍。在其他神经退行性疾病中也有疾病相关的少突胶质细胞特征的证据。包括老年痴呆症,肌萎缩侧索硬化症,帕金森病,和亨廷顿病。这里,我们评估了抗ATXN3反义寡核苷酸(ASO)治疗对症状前SCA3小鼠少突胶质细胞功能障碍的影响.我们报告了严重的，但可以修改，在SCA3疾病早期，由突变ATXN3的毒性功能获得引起的少突胶质细胞成熟缺陷，生物化学，并在功能上使用抗ATXN3ASO解救。我们的结果强调了ASO疗法在神经退行性疾病中的有希望的应用，除了受影响的神经元群体外，还需要神经胶质靶向。
