The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFκB pathway dysregulation
Open accessAbstract
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.
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Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641
Self-citationMicroglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies
Jimenez-Sanchez, M., Licitra, F., Underwood, B. R., & Rubinsztein, D. C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024240 · Cited by 507
Elusive roles for reactive astrocytes in neurodegenerative diseases
Ben Haim, L., Carrillo-de Sauvage, M.-A., Ceyzériat, K., & Escartin, C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00278 · Cited by 453
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
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Metadata
- Authors
- Träger, U., Andre, R., Lahiri, N., Magnusson-Lind, A., Weiss, A., Grueninger, S., McKinnon, C., Sirinathsinghji, E., Kahlon, S., Pfister, E. L., Moser, R., Hummerich, H., Antoniou, M., Bates, G. P., Luthi-Carter, R., Lowdell, M. W., Björkqvist, M., Ostroff, G. R., Aronin, N., & Tabrizi, S. J.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-01-22
- Volume
- 137
- Issue
- 3
- Pages
- 819-833
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2003551942
- Cited by
- 192
- References
- 10
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- green
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- Träger, U., Andre, R., Lahiri, N., Magnusson-Lind, A., Weiss, A., Grueninger, S., McKinnon, C., Sirinathsinghji, E., Kahlon, S., Pfister, E. L., Moser, R., Hummerich, H., Antoniou, M., Bates, G. P., Luthi-Carter, R., Lowdell, M. W., Björkqvist, M., Ostroff, G. R., Aronin, N., & Tabrizi, S. J. (2014). HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFκB pathway dysregulation. Brain. https://doi.org/10.1093/brain/awt355
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