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HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFκB pathway dysregulation

Ulrike Träger, Ralph Andre, Nayana Lahiri, Anna Magnusson-Lind, Andreas Weiss, Stephan Grueninger, Chris McKinnon, Eva Sirinathsinghji, Shira Kahlon, Edith L. Pfister, Roger Moser, Holger Hummerich, Michael Antoniou, Gillian P. Bates, Ruth Luthi-Carter, Mark W. Lowdell, Maria Björkqvist, Gary R. Ostroff, Neil Aronin, Sarah J. Tabrizi
DOI: http://dx.doi.org/10.1093/brain/awt355 819-833 First published online: 22 January 2014


Huntington’s disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington’s disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington’s disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NFκB pathway, whereby it interacts with IKKγ, leads to increased degradation of IκB and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signalling pathways are also observed. Using a novel method of small interfering RNA delivery to lower huntingtin expression, we show reversal of disease-associated alterations in cellular function–the first time this has been demonstrated in primary human cells. Glucan-encapsulated small interfering RNA particles were used to lower huntingtin levels in human Huntington’s disease monocytes/macrophages, resulting in a reversal of huntingtin-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce glucan-encapsulated small interfering RNA particles as tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of immune cell-directed HTT-lowering as a therapeutic in Huntington’s disease.

  • Huntington’s disease
  • immunology
  • myeloid cells
  • gene lowering
  • Abbreviations
    β1,3-d-glucan-encapsulated small interfering RNA particle
    time resolved fluorescence resonance energy transfer
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