Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we studied transcriptomic changes in HD human, HD mice, and Drosophila expressing human mutant Huntingtin (mHTT) in either glia, neurons or both. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, mitigating glial pathogenesis by dNRXN3 knockdown was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the excitotoxicity that characterizes HD.

中文翻译：

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在亨廷顿舞蹈症的果蝇模型中，调节与突触功能有关的神经胶质基因可减轻发病机理和行为缺陷。

关于神经退行性疾病的大多数研究都集中在神经元上，而神经胶质有助于形成和维持突触，在这些情况下突触的丧失如此突出。为了研究神经胶质对亨廷顿病（HD）的贡献，我们研究了神经胶质，神经元或两者中的人类，HD小鼠和表达果蝇的人类突变型亨廷顿蛋白（mHTT）的转录组变化。在这三个物种中，大部分保守基因一致失调。我们在高通量行为分析中测试了这些基因，发现与突触组装有关的基因下调减轻了发病机理和行为缺陷。令我们惊讶的是，通过敲低dNRXN3来减轻神经胶质的发病机理足以改善神经元中表达mHTT的苍蝇的表型，这表明mHTT' 胶质细胞的毒性作用遍布整个大脑。这支持了其中抑制突触功能具有保护作用的模型，因为它减弱了表征HD的兴奋性毒性。