Interleukin-6 deficiency exacerbates Huntington’s disease model phenotypes
Author(s)Wertz, Mary H.; Pineda, S. Sebastian; Lee, Hyeseung; Kulicke, Ruth; Kellis, Manolis; Heiman, Myriam; ... Show more Show less
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Huntington’s disease (HD) is an incurable neurodegenerative disorder caused by CAG trinucleotide expansions in the huntingtin gene. Markers of both systemic and CNS immune activation and inflammation have been widely noted in HD and mouse models of HD. In particular, elevation of the pro-inflammatory cytokine interleukin-6 (IL-6) is the earliest reported marker of immune activation in HD, and this elevation has been suggested to contribute to HD pathogenesis. To test the hypothesis that IL-6 deficiency would be protective against the effects of mutant huntingtin, we generated R6/2 HD model mice that lacked IL-6. Contrary to our prediction, IL-6 deficiency exacerbated HD-model associated behavioral phenotypes. Single nuclear RNA Sequencing (snRNA-seq) analysis of striatal cell types revealed that IL-6 deficiency led to the dysregulation of various genes associated with synaptic function, as well as the BDNF receptor Ntrk2. These data suggest that IL-6 deficiency exacerbates the effects of mutant huntingtin through dysregulation of genes of known relevance to HD pathobiology in striatal neurons, and further suggest that modulation of IL-6 to a level that promotes proper regulation of genes associated with synaptic function may hold promise as an HD therapeutic target.
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and Memory; Broad Institute of MIT and Harvard; Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Wertz, Mary H. et al. "Interleukin-6 deficiency exacerbates Huntington’s disease model phenotypes." Molecular Neurodegeneration 15 (May 2020): no. 29 doi 10.1186/s13024-020-00379-3 ©2020 Author(s)
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