期刊
ELIFE
卷 10, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.64564
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资金
- Natural Science Foundation of China [31970747, 31601105, 81870990, 81925012]
- National Research Centre [T32 GM008307]
- NLM [T15 LM007093]
- NIH [S10 OD016167, R01AG057339]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [P50HD103555]
- CHDI Foundation [I-0986]
Research shows that glia cells play a crucial role in the formation and maintenance of synapses in neurodegenerative diseases. Lowering genes involved in synapse assembly can alleviate pathological and behavioral deficits. Conserved gene dysregulation is observed in patients with neurodegenerative diseases, fruit flies, and mice.
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.
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