TY - JOUR TI - Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis AU - Onur, Tarik Seref AU - Laitman, Andrew AU - Zhao, He AU - Keyho, Ryan AU - Kim, Hyemin AU - Wang, Jennifer AU - Mair, Megan AU - Wang, Huilan AU - Li, Lifang AU - Perez, Alma AU - de Haro, Maria AU - Wan, Ying-Wooi AU - Allen, Genevera AU - Lu, Boxun AU - Al-Ramahi, Ismael AU - Liu, Zhandong AU - Botas, Juan A2 - Eisen, Michael B A2 - Thompson, Leslie M VL - 10 PY - 2021 DA - 2021/04/19 SP - e64564 C1 - eLife 2021;10:e64564 DO - 10.7554/eLife.64564 UR - https://doi.org/10.7554/eLife.64564 AB - 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. KW - Huntington's disease KW - neurodegeneration KW - glia KW - synaptic biology KW - excitotoxicity KW - high-throughput experimentation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -