RRC ID 70374
Author 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.
Title Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis.
Journal Elife
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 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.
Volume 10
Published 2021-4-19
DOI 10.7554/eLife.64564
PII 64564
PMID 33871358
PMC PMC8149125
MeSH Animals Behavior, Animal Brain / metabolism* Brain / pathology Brain / physiopathology Case-Control Studies Cell Adhesion Molecules, Neuronal / genetics Cell Adhesion Molecules, Neuronal / metabolism Cell Line Disease Models, Animal Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster Electrical Synapses / metabolism* Electrical Synapses / pathology Female Gene Regulatory Networks Humans Huntingtin Protein / genetics Huntingtin Protein / metabolism* Huntington Disease / genetics Huntington Disease / metabolism* Huntington Disease / pathology Huntington Disease / physiopathology Locomotion Male Mice, Transgenic Mutation Neuroglia / metabolism* Neuroglia / pathology Synaptic Transmission* Transcriptome alpha 1-Antitrypsin / genetics alpha 1-Antitrypsin / metabolism
IF 7.08
Drosophila 11144R-3