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Nat Neurosci. 2014 Apr;17(4):513-21. doi: 10.1038/nn.3668. Epub 2014 Mar 2.

Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors.

Author information

1
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
2
Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California, USA.
3
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California, USA.
4
1] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Ludwig Institute for Cancer Research, La Jolla, California, USA.
5
Department of BioSciences and Center for Stem Cell Research, Università degli Studi di Milano, Milan, Italy.
6
1] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [2] Ludwig Institute for Cancer Research, La Jolla, California, USA.
7
1] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [2] Department of Medicine, University of California, La Jolla, San Diego, California, USA.

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an extended polyglutamine repeat in the N terminus of the Huntingtin protein (HTT). Reactive microglia and elevated cytokine levels are observed in the brains of HD patients, but the extent to which neuroinflammation results from extrinsic or cell-autonomous mechanisms in microglia is unknown. Using genome-wide approaches, we found that expression of mutant Huntingtin (mHTT) in microglia promoted cell-autonomous pro-inflammatory transcriptional activation by increasing the expression and transcriptional activities of the myeloid lineage-determining factors PU.1 and C/EBPs. We observed elevated levels of PU.1 and its target genes in the brains of mouse models and individuals with HD. Moreover, mHTT-expressing microglia exhibited an increased capacity to induce neuronal death ex vivo and in vivo in the presence of sterile inflammation. These findings suggest a cell-autonomous basis for enhanced microglia reactivity that may influence non-cell-autonomous HD pathogenesis.

PMID:
24584051
PMCID:
PMC4113004
DOI:
10.1038/nn.3668
[Indexed for MEDLINE]
Free PMC Article
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