Journal
NEURON
Volume 107, Issue 5, Pages 891-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2020.06.021
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Funding
- CHDI Foundation
- NIH/NINDS [NS065013, 1 R01 NS100802]
- Broderick fund for Phytocannabinoid Research at MIT
- JPB Foundation
- NIH [5T32EB019940-05, R25MH101076]
- NIH NIA NIMH NINDS NHGRI [R01AG062335, R01AG058002, RF1AG054012, RF1AG062377, R01MH109978, U01MH119509, U01NS110453, R01HG008155]
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The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.
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