Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, H2X 0A9, Canada.
Department of Biochemistry, University of Montreal, Montreal, Quebec, H3T 1J4, Canada.
Neurotherapeutics. 2021 Apr;18(2):1151-1165. doi: 10.1007/s13311-020-00993-5. Epub 2021 Mar 29.
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a polyglutamine expansion disease arising from a trinucleotide CAG repeat expansion in exon 10 of the gene ATXN3. There are no effective pharmacological treatments for MJD, thus the identification of new pathogenic mechanisms, and the development of novel therapeutics is urgently needed. In this study, we performed a comprehensive, blind drug screen of 3942 compounds (many FDA approved) and identified small molecules that rescued the motor-deficient phenotype in transgenic ATXN3 Caenorhabditis elegans strain. Out of this screen, five lead compounds restoring motility, protecting against neurodegeneration, and increasing the lifespan in ATXN3-CAG89 mutant worms were identified. These compounds were alfacalcidol, chenodiol, cyclophosphamide, fenbufen, and sulfaphenazole. We then investigated how these molecules might exert their neuroprotective properties. We found that three of these compounds, chenodiol, fenbufen, and sulfaphenazole, act as modulators for TFEB/HLH-30, a key transcriptional regulator of the autophagy process, and require this gene for their neuroprotective activities. These genetic-chemical approaches, using genetic C. elegans models for MJD and the screening, are promising tools to understand the mechanisms and pathways causing neurodegeneration, leading to MJD. Positively acting compounds may be promising candidates for investigation in mammalian models of MJD and preclinical applications in the treatment of this disease.
脊髓小脑共济失调 3 型（SCA3），也称为 Machado-Joseph 病（MJD），是一种多聚谷氨酰胺扩展疾病，由 ATXN3 基因外显子 10 中的三核苷酸 CAG 重复扩展引起。目前尚无有效的药物治疗 MJD，因此迫切需要确定新的发病机制并开发新的治疗方法。在这项研究中，我们对 3942 种化合物（包括许多 FDA 批准的化合物）进行了全面、盲法药物筛选，并鉴定出了可挽救转 ATXN3 基因的秀丽隐杆线虫运动缺陷表型的小分子。在这次筛选中，发现了 5 种可恢复运动能力、预防神经退行性变并延长 ATXN3-CAG89 突变线虫寿命的先导化合物。这些化合物分别是阿尔法骨化醇、鹅去氧胆酸、环磷酰胺、芬布芬和磺胺苯吡唑。然后，我们研究了这些分子如何发挥其神经保护作用。我们发现，这 3 种化合物，即鹅去氧胆酸、芬布芬和磺胺苯吡唑，作为 TFEB/HLH-30 的调节剂，而 TFEB/HLH-30 是自噬过程的关键转录调节因子，这些化合物的神经保护作用需要该基因。这些基于遗传的化学方法，使用 MJD 的遗传秀丽隐杆线虫模型进行筛选，是了解导致神经退行性变的机制和途径的有前途的工具，可导致 MJD。具有积极作用的化合物可能是研究 MJD 哺乳动物模型和该疾病临床前应用的有希望的候选药物。
