How the mutant huntingtin gene (mHTT) causes neuronal death in Huntington disease (HD) is not known. Previous studies investigating the basis of its toxicity have not focused on striatal spiny projection neurons of the indirect pathway (iSPNs), which are the most vulnerable cell type in HD. Lee et al. used translating ribosome affinity purification and single-nucleus RNA sequencing (snRNA-seq) to find alterations in gene expression in different cell types in HD mouse models, and nRNA-seq to compare gene expression in different cell types in post-mortem samples from individuals with HD versus non-HD controls. Mitochondrial RNAs (mtRNAs) and RNAs involved in mitochondrial oxidative phosphorylation were upregulated and downregulated, respectively, in iSPNs from HD brain tissue, and immunoprecipitation revealed that mtRNAs bind to the innate immune sensor protein kinase R. Thus, mHTT may induce mtRNA release in iSPNs, leading to innate immune activation.
Lee, H. et al. Cell-type-specific transcriptomics reveals that mutant huntingtin leads to mitochondrial RNA release and neuronal innate immune activation. Neuron https://doi.org/10.1016/j.neuron.2020.06.021 (2020)