PDF(Pubmed)
Abstract：
BACKGROUND: PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies.
METHODS: A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington\'s disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q94). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity.
RESULTS: The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimine was due to the stimulation of mitochondrial biogenesis by peroxisome proliferator-activated receptor gamma (PPARγ). In agreement with this, clofazimine rescued mitochondrial dysfunction triggered by Htt-Q94 expression. Importantly, clofazimine also limited polyQ toxicity in developing zebrafish and neuron-specific worm models of polyQ disease.
CONCLUSIONS: Our results support the potential of repurposing the antimicrobial drug clofazimine for the treatment of polyQ diseases.
BACKGROUND: A full list of funding sources can be found in the acknowledgments section.
METHODS: A high-throughput chemical screen was conducted to identify drugs that lower the toxicity of a protein containing the first exon of Huntington\'s disease (HD) protein huntingtin (HTT) harbouring 94 glutamines (Htt-Q94). Candidate drugs were tested in a wide range of in vitro and in vivo models of polyQ toxicity.
RESULTS: The chemical screen identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models. Computational analyses of transcriptional signatures revealed that the effect of clofazimine was due to the stimulation of mitochondrial biogenesis by peroxisome proliferator-activated receptor gamma (PPARγ). In agreement with this, clofazimine rescued mitochondrial dysfunction triggered by Htt-Q94 expression. Importantly, clofazimine also limited polyQ toxicity in developing zebrafish and neuron-specific worm models of polyQ disease.
CONCLUSIONS: Our results support the potential of repurposing the antimicrobial drug clofazimine for the treatment of polyQ diseases.
BACKGROUND: A full list of funding sources can be found in the acknowledgments section.
摘要：
背景：PolyQ疾病是由CAG重复序列扩增引起的常染色体显性神经退行性疾病。虽然进展缓慢，这些疾病最终是致命的，缺乏有效的治疗方法。
方法：进行了高通量化学筛选，以鉴定降低含有亨廷顿病（HD）蛋白亨廷顿蛋白（HTT）第一个外显子的蛋白质（Htt-Q94）的毒性的药物。在多种体外和体内polyQ毒性模型中测试了候选药物。
结果：化学筛选确定了抗麻风药物氯法齐明，随后在几个体外模型中进行了验证。转录特征的计算分析表明，氯法齐明的作用是由于过氧化物酶体增殖物激活受体γ（PPARγ）刺激线粒体生物发生。同意这一点，氯法齐明拯救由Htt-Q94表达引发的线粒体功能障碍。重要的是,氯法齐明还限制了polyQ在发展斑马鱼和polyQ疾病的神经元特异性蠕虫模型中的毒性。
结论：我们的结果支持将抗菌药物氯法齐明重新用于治疗polyQ疾病的潜力。
背景：资金来源的完整列表可以在确认部分找到。
方法：进行了高通量化学筛选，以鉴定降低含有亨廷顿病（HD）蛋白亨廷顿蛋白（HTT）第一个外显子的蛋白质（Htt-Q94）的毒性的药物。在多种体外和体内polyQ毒性模型中测试了候选药物。
结果：化学筛选确定了抗麻风药物氯法齐明，随后在几个体外模型中进行了验证。转录特征的计算分析表明，氯法齐明的作用是由于过氧化物酶体增殖物激活受体γ（PPARγ）刺激线粒体生物发生。同意这一点，氯法齐明拯救由Htt-Q94表达引发的线粒体功能障碍。重要的是,氯法齐明还限制了polyQ在发展斑马鱼和polyQ疾病的神经元特异性蠕虫模型中的毒性。
结论：我们的结果支持将抗菌药物氯法齐明重新用于治疗polyQ疾病的潜力。
背景：资金来源的完整列表可以在确认部分找到。
