Mutant Huntingtin Promotes Autonomous Microglia Activation Via Myeloid Lineage-determining Factors

Overview

Journal Nat Neurosci

Date 2014 Mar 4

PMID 24584051

Citations 169

Authors

Andrea Crotti

Christopher Benner

Bilal E Kerman

David Gosselin

Clotilde Lagier-Tourenne

Chiara Zuccato

Elena Cattaneo

Fred H Gage

Don W Cleveland

Christopher K Glass

Affiliations

Soon will be listed here.

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.

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