HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation.
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.
1 UCL Institute of Neurology, Department of Neurodegenerative Disease, London, UK.
Ulrike
U
Träger
Ralph
R
Andre
Nayana
N
Lahiri
Anna
A
Magnusson-Lind
Andreas
A
Weiss
Stephan
S
Grueninger
Chris
C
McKinnon
Eva
E
Sirinathsinghji
Shira
S
Kahlon
Edith L
EL
Pfister
Roger
R
Moser
Holger
H
Hummerich
Michael
M
Antoniou
Gillian P
GP
Bates
Ruth
R
Luthi-Carter
Mark W
MW
Lowdell
Maria
M
Björkqvist
Gary R
GR
Ostroff
Neil
N
Aronin
Sarah J
SJ
Tabrizi
D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D007113:Immunity, Innate / Q000235:genetics; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000627:therapeutic use; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D020298:U937 Cells
C086055:HTT protein, human; D000071058:Huntingtin Protein; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering
Huntington’s disease; gene lowering; immunology; myeloid cells