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 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.
Competing Interest Statement
The authors have declared no competing interest.
