Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 St-Denis Street, Montreal, Quebec H2X 0A9, Canada; Department of Biochemistry, University of Montreal, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 St-Denis Street, Montreal, Quebec H2X 0A9, Canada; Department of Biochemistry, University of Montreal, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada; Department of Neuroscience, University of Montreal, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada.
Exp Neurol. 2021 Mar;337:113544. doi: 10.1016/j.expneurol.2020.113544. Epub 2020 Dec 5.
Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common form of dominantly inherited ataxia worldwide. This disease is caused by an expanded CAG repeat in the coding region of ATXN3. Due to our incomplete understanding of mechanisms and molecular pathways related to this disease, there are no therapies that successfully treat core MJD patients. Therefore, the identification of new candidate targets related to this disease is needed. In this study, we performed a large-scale RNA interference (RNAi) screen of 387 transcription factor genes leading to the identification of several modifiers (suppressors and enhancers) of impaired motility phenotypes in a mutant ATXN3 transgenic C. elegans model. We showed that inactivation of one particular gene, fkh-2/FOXG1, enhanced the motility defect, neurodegeneration and reduced longevity in our MJD models. Opposite to genetic inactivation, the overexpression of fkh-2 rescued the impaired motility, shortened-lifespan, and neurodegeneration phenotypes of mutant ATXN3 transgenics. We found that overexpression of FKH-2/FOXG1 in ATXN3 mutant worms is neuroprotective. Using our transgenic ATXN3 C. elegans models and the screening of an RNAi library, we gained insights into the pathways contributing to neurodegeneration, and found that FKH-2/FOXG1 has neuroprotective activity. These findings may aid the development of novel therapeutic interventions for MJD.
马查多-约瑟夫病（MJD），又称脊髓小脑共济失调 3 型（SCA3），是全世界最常见的显性遗传性共济失调类型。这种疾病是由 ATXN3 编码区中 CAG 重复扩增引起的。由于我们对与这种疾病相关的机制和分子途径的了解不完全，因此没有成功治疗核心 MJD 患者的疗法。因此，需要确定与这种疾病相关的新候选靶点。在这项研究中，我们对 387 个转录因子基因进行了大规模 RNA 干扰（RNAi）筛选，导致在突变型 ATXN3 转基因秀丽隐杆线虫模型中鉴定出几种运动表型受损的调节剂（抑制剂和增强子）。我们表明，特定基因 fkh-2/FOXG1 的失活增强了我们的 MJD 模型中的运动缺陷、神经退行性变和寿命缩短。与基因失活相反，fkh-2 的过表达挽救了突变型 ATXN3 转基因动物的运动缺陷、寿命缩短和神经退行性变表型。我们发现，FKH-2/FOXG1 在 ATXN3 突变型蠕虫中的过表达具有神经保护作用。使用我们的 ATXN3 转基因秀丽隐杆线虫模型和 RNAi 文库筛选，我们深入了解了导致神经退行性变的途径，并发现 FKH-2/FOXG1 具有神经保护活性。这些发现可能有助于开发治疗 MJD 的新疗法。
