Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis

Abstract

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 <i>Drosophila</i> expressing human mutant <i>Huntingtin</i> (m<i>HTT</i>) 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 d<i>NRXN3</i> function in glia was sufficient to improve the phenotype of flies expressing m<i>HTT</i> 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.