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HTT-lowering reverses Huntington's disease immune dysfunction caused by NF kappa B pathway dysregulation

In English

Författare

  • Ulrike Traeger
  • 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
Visa allt

Summary, in English

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.

Publiceringsår

2014

Språk

Engelska

Sidor

819-833

Publikation/Tidskrift/Serie

Brain

Volym

137

Dokumenttyp

Artikel i tidskrift

Förlag

Oxford University Press

Ämne

  • Neurology

Nyckelord

  • Huntington's disease
  • immunology
  • myeloid cells
  • gene lowering

Status

Published

Forskningsgrupp

  • Biomarkers in Brain Disease

ISBN/ISSN/Övrigt

  • ISSN: 1460-2156