HTT-lowering reverses Huntington's disease immune dysfunction caused by NFkappaB pathway dysregulation
Pfister, Edith L.
Bates, Gillian P.
Lowdell, Mark W.
Ostroff, Gary R.
Tabrizi, Sarah J.
Student AuthorsEdith. L. Pfister
UMass Chan AffiliationsDepartment of Medicine, Division of Endocrinology and Metabolism
Program in Molecular Medicine
Document TypeJournal Article
KeywordsGene Expression Regulation; Humans; Huntington Disease; Immunity, Innate; Myeloid Cells; NF-kappa B; Nerve Tissue Proteins; RNA, Small Interfering; Signal Transduction; U937 Cells
Genetics and Genomics
Nervous System Diseases
Neuroscience and Neurobiology
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AbstractHuntington'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 NFkappaB pathway, whereby it interacts with IKKgamma, leads to increased degradation of IkappaB 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.
SourceBrain. 2014 Mar;137(Pt 3):819-33. doi: 10.1093/brain/awt355. Epub 2014 Jan 22. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33397
Related ResourcesLink to Article in PubMed