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.
RNA-sequencing data produced by this study has been deposited in GEO under accession code GSE157287. We have provided source data for all main figures 2, 3,4,5, and 6 as well as for supplemental figures 4,5, and 6. Codes for analyzing gene expression, networks, and Drosophila behavior are provided.
RNA-sequencing of Drosophila expressing mutant Huntingtin in neurons or gliaNCBI Gene Expression Omnibus, GSE157287.
hESC-based human glial chimeric mice reveal glial differentiation defects in Huntington diseaseNCBI Gene Expression Omnibus, GSE105041.
Transcriptome profiling in knock-in mouse models of Huntington's disease [striatum; cortex; liver; tissue survey]NCBI Gene Expression Omnibus, GSE65776.
Human cerebellum, frontal cortex [BA4, BA9] and caudate nucleus HD tissue experimentNCBI Gene Expression Omnibus, GSE3790.
This work was supported by grants to J.B. from NIH/ NIA (R01AG057339) and CHDI. B.L. is sponsored by Natural Science Foundation of China (31970747, 31601105, 81870990, 81925012). T.O. and M.M. were supported by the NIGMS Ruth L. Kirschstein National Research Service Award (NRSA) Predoctoral Institutional Research Training Grant (T32 GM008307) provided to the Genetics & Genomics Graduate Program at Baylor College of Medicine. A.L. was supported by Baylor College of Medicine Medical Scientist Training Program and the NLM Training Program in Biomedical Informatics and Data Science (T15 LM007093) at the Gulf Coast Consortium. The High Throughput Behavioral Screening core at the Jan and Dan Duncan Neurological Research Institute was supported by generous philanthropy from the Hildebrand family foundation. The project was also supported by a shared Instrumentation grant from the NIH (S10 OD016167) and Baylor College of Medicine IDDRC Grant Number P50HD103555 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for use of the Microscopy Core facilities, the Cell and Tissue Pathogenesis Core and the RNA In Situ Hybridization Core facility with the expert assistance of Dr. Cecilia Ljungberg. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health.
- Michael B Eisen, University of California, Berkeley, United States
- Received: November 3, 2020
- Accepted: April 19, 2021
- Accepted Manuscript published: April 19, 2021 (version 1)
© 2021, Onur et al.
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