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.
Highlights
Neurodegenerative conditions involve a complex cascade of events that takes many years to unfold.Even in the case of inherited disorders due to mutation in a single gene, such as Huntington’s Disease (HD), the downstream ramifications at the molecular level are astonishingly broad
We identified 1,852 downregulated and 1,941 upregulated differentially expressed genes (DEGs) in patients with Huntington’s disease (HD) compared to healthy individuals (Figure 1B)
We reanalyzed published RNA-seq data from mouse striata, using an allelic series of knock-in mouse models with varying CAG-repeat lengths at six months of age (Langfelder et al, 2016). Because it is unclear which CAG tract length in mice most faithfully recapitulates HD pathogenesis, the triplet repeat length was treated as a continuous trait, and we narrowed our analysis to DEGs that correlate with increasing CAG repeat length
Summary
Neurodegenerative conditions involve a complex cascade of events that takes many years to unfold.Even in the case of inherited disorders due to mutation in a single gene, such as Huntington’s Disease (HD), the downstream ramifications at the molecular level are astonishingly broad. Caused by a CAG repeat expansion in Huntingtin (HTT) (The Huntington’s Disease Collaborative Research Group, 1993), HD pathology is prominent in the striatum and cortex, yet transcriptomic studies consistently reveal thousands of changes in gene expression across the brain and different neuronal cell types, involving pathways ranging from autophagy to vesicular trafficking (Saudou and Humbert, 2016). Recent studies using single-cell sequencing in astrocytes isolated from post-mortem tissue from HD patients and mouse models of HD (Al-Dalahmah et al, 2020; Diaz-Castro et al, 2019) developed molecular profiles that distinguish HD-affected astrocytes from astrocytes found in healthy brain tissue, but the physiological consequences of the gene expression changes were unclear
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