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

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Fältnamn	Indikatorer	Metadata
000		04210naa a2200577 4500
001		oai:lup.lub.lu.se:1a4c1ad4-992e-484c-8b7d-adf5686ee455
003		SwePub
008		160401s2014 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://lup.lub.lu.se/record/43636352 URI
024	7	a https://doi.org/10.1093/brain/awt3552 DOI
040		a (SwePub)lu
041		a engb eng
042		9 SwePub
072	7	a art2 swepub-publicationtype
072	7	a ref2 swepub-contenttype
100	1	a Traeger, Ulrike4 aut
245	1 0	a HTT-lowering reverses Huntington's disease immune dysfunction caused by NF kappa B pathway dysregulation
264		c 2014-01-22
264	1	b Oxford University Press (OUP),c 2014
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Neurologi0 (SwePub)302072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Neurology0 (SwePub)302072 hsv//eng
653		a Huntington's disease
653		a immunology
653		a myeloid cells
653		a gene lowering
700	1	a Andre, Ralph4 aut
700	1	a Lahiri, Nayana4 aut
700	1	a Magnusson-Lind, Annau Lund University,Lunds universitet,Biomarkörer vid hjärnsjukdomar,Forskargrupper vid Lunds universitet,Biomarkers in Brain Disease,Lund University Research Groups4 aut0 (Swepub:lu)med-a_m
700	1	a Weiss, Andreas4 aut
700	1	a Grueninger, Stephan4 aut
700	1	a McKinnon, Chris4 aut
700	1	a Sirinathsinghji, Eva4 aut
700	1	a Kahlon, Shira4 aut
700	1	a Pfister, Edith L.4 aut
700	1	a Moser, Roger4 aut
700	1	a Hummerich, Holger4 aut
700	1	a Antoniou, Michael4 aut
700	1	a Bates, Gillian P.4 aut
700	1	a Luthi-Carter, Ruth4 aut
700	1	a Lowdell, Mark W.4 aut
700	1	a Björkqvist, Mariau Lund University,Lunds universitet,Biomarkörer vid hjärnsjukdomar,Forskargrupper vid Lunds universitet,Biomarkers in Brain Disease,Lund University Research Groups4 aut0 (Swepub:lu)farm-mbj
700	1	a Ostroff, Gary R.4 aut
700	1	a Aronin, Neil4 aut
700	1	a Tabrizi, Sarah J.4 aut
710	2	a Biomarkörer vid hjärnsjukdomarb Forskargrupper vid Lunds universitet4 org
773	0	t Braind : Oxford University Press (OUP)g 137, s. 819-833q 137<819-833x 1460-2156x 0006-8950
856	4	u http://dx.doi.org/10.1093/brain/awt355y FULLTEXT
856	4	u https://academic.oup.com/brain/article-pdf/137/3/819/13797635/awt355.pdf
856	4 8	u https://lup.lub.lu.se/record/4363635
856	4 8	u https://doi.org/10.1093/brain/awt355

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