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

Traeger, U and Andre, R and Lahiri, N and Magnusson-Lind, A and Weiss, A and Grueninger, S and McKinnon, C and Sirinathsinghji, E and Kahlon, S and Pfister, EL and Moser, R and Hummerich, H and Antoniou, M and Bates, GP and Luthi-Carter, R and Lowdell, MW and Bjoerkqvist, M and Ostroff, GR and Aronin, N and Tabrizi, SJ (2014) HTT-lowering reverses Huntington's disease immune dysfunction caused by NF kappa B pathway dysregulation. BRAIN. pp. 819-833.

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

Item Type: Article
Additional Information: NIBR author: Weiss, A institute: NIBR contributor address: UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England s.tabrizi@ucl.ac.uk; UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England, Lund Univ, Brain Dis Biomarker Unit, Dept Expt Med Sci, Wallenberg Neurosci Ctr, Lund, Sweden ; Novartis Inst BioMed Res, Basel, Switzerland ; Guys Hosp, Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England ; Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA ; Univ Massachusetts, Sch Med, Dept Med, Div Endocrinol & Metab, Worcester, MA USA ; Ecole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland ; Ecole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland, Univ Leicester, Dept Cell Physiol & Pharmacol, Coll Med, Leicester LE1 9HN, Leics, England ; UCL, Dept Haematol, London, England ; Lund Univ, Brain Dis Biomarker Unit, Dept Expt Med Sci, Wallenberg Neurosci Ctr, Lund, Sweden ; UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England; Tabrizi, S J; UCL Inst Neurol, Dept Neurodegenerat Dis, Queen Sq, London WC1N 3BG, England
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22586

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