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

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 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.

• Authors: 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
• Journal: Brain : a journal of neurology (Brain) Vol. 137 Issue Pt 3 Pg. 819-33 (Mar 2014) ISSN: 1460-2156 [Electronic] England
• PMID: 24459107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HTT protein, human
• Huntingtin Protein
• NF-kappa B
• Nerve Tissue Proteins
• RNA, Small Interfering

Topics

• Gene Expression Regulation (immunology)
• Humans
• Huntingtin Protein
• Huntington Disease (genetics, metabolism, pathology)
• Immunity, Innate (genetics)
• Myeloid Cells (immunology, pathology)
• NF-kappa B (antagonists & inhibitors, physiology)
• Nerve Tissue Proteins (antagonists & inhibitors, biosynthesis, genetics)
• RNA, Small Interfering (therapeutic use)
• Signal Transduction (genetics, immunology)
• U937 Cells