Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis.
Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis.
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下调参与突触功能的神经胶质基因可减轻亨廷顿病的发病机制
DOI：
10.7554/elife.64564
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发表时间：
2021-04-19
期刊：
影响因子：
7.7
通讯作者：
Botas J
中科院分区：
文献类型：
--
作者：
Onur TS;Laitman A;Zhao H;Keyho R;Kim H;Wang J;Mair M;Wang H;Li L;Perez A;de Haro M;Wan YW;Allen G;Lu B;Al-Ramahi I;Liu Z;Botas J
大多数关于神经退行性疾病的研究都集中在神经元上，但神经胶质帮助形成和维持突触，突触的丢失在这些情况下是如此突出。为了探讨胶质细胞在亨廷顿病(HD)中的作用，我们描述了表达人突变体Huntingtin(MHTT)的果蝇在神经胶质细胞和神经元中的基因表达变化，并将这些变化与HD人和HD小鼠纹状体中观察到的变化进行了比较。很大一部分保守基因在这三个物种中都存在一致的失调；我们在高通量行为测试中测试了这些基因，发现参与突触组装的基因下调可以减轻发病和行为缺陷。令我们惊讶的是，降低胶质细胞中dNRXN3的功能足以改善在神经元中表达mHTT的果蝇的表型，这表明mHTT在胶质细胞中的毒性效应遍及整个大脑。这支持了一种模型，在该模型中，抑制突触功能是保护性的，因为它减弱了HD的兴奋毒性。
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 profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. 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, reducing dNRXN3 function in glia 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.