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

U Träger, R Andre, N Lahiri, A Magnusson-Lind, A Weiss, S Grueninger, C McKinnon, E Sirinathsinghji, S Kahlon, EL Pfister, R Moser, H Hummerich, Michael Antoniou, Gillian Bates, R Luthi-Carter, MW Lowdell, M Björkqvist, GR Ostroff, N Aronin, SJ Tabrizi

Research output: Contribution to journalArticlepeer-review

123 Citations (Scopus)

Abstract

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 NF kappa B pathway, whereby it interacts with IKK gamma, leads to increased degradation of I kappa B 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.

Original languageEnglish
Pages (from-to)819-833
Number of pages15
JournalBrain
Volume137
Issue number3
DOIs
Publication statusPublished - Mar 2014

Keywords

  • Huntington's disease
  • immunology
  • myeloid cells
  • gene lowering
  • GENOME-WIDE ASSOCIATION
  • MUTANT HUNTINGTIN
  • ALZHEIMERS-DISEASE
  • TRANSCRIPTION FACTOR
  • IDENTIFIES VARIANTS
  • KINASE COMPLEX
  • MOUSE MODELS
  • TNF-ALPHA
  • ACTIVATION
  • CELLS

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