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IKKβ and mutant huntingtin interactions regulate the expression of IL-34: implications for microglial-mediated neurodegeneration in HD

Khoshnan, Ali and Sabbaugh, Adam and Calamini, Barbara and Marinero, Steven A. and Dunn, Denise E. and Yoo, Jung Hyun and Ko, Jan and Lo, Donald C. and Patterson, Paul H. (2017) IKKβ and mutant huntingtin interactions regulate the expression of IL-34: implications for microglial-mediated neurodegeneration in HD. Human Molecular Genetics, 26 (21). pp. 4267-4277. ISSN 0964-6906. https://resolver.caltech.edu/CaltechAUTHORS:20171009-124506815

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Abstract

Neuronal interleukin-34 (IL-34) promotes the expansion of microglia in the central nervous system—microglial activation and expansion are in turn implicated in the pathogenesis of Huntington‘s disease (HD). We thus examined whether the accumulation of an amyloidogenic exon-1 fragment of mutant huntingtin (mHTTx1) modulates the expression of IL-34 in dopaminergic neurons derived from a human embryonic stem cell line. We found that mHTTx1 aggregates induce IL-34 production selectively in post-mitotic neurons. Exposure of neurons to DNA damaging agents or the excitotoxin NMDA elicited similar results suggesting that IL-34 induction may be a general response to neuronal stress including the accumulation of misfolded mHTTx1. We further determined that knockdown or blocking the activity of IκB kinase beta (IKKβ) prevented the aggregation of mHTTx1 and subsequent IL-34 production. While elevated IL-34 itself had no effect on the aggregation or the toxicity of mHTTx1 in neuronal culture, IL-34 expression in a rodent brain slice model with intact neuron-microglial networks exacerbated mHTTx1-induced degeneration of striatal medium-sized spiny neurons. Conversely, an inhibitor of the IL-34 receptor reduced microglial numbers and ameliorated mHTTx1-mediated neurodegeneration. Together, these findings uncover a novel function for IKKβ/mHTTx1 interactions in regulating IL-34 production, and implicate a role for IL-34 in non-cell-autonomous, microglial-dependent neurodegeneration in HD.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1093/hmg/ddx315DOIArticle
https://academic.oup.com/hmg/article/26/21/4267/4082705/IKK%CE%B2-and-mutant-huntingtin-interactions-regulatePublisherArticle
Additional Information:© 2017 The Author. Published by Oxford University Press. Received: 10 May 2017; Revision Received: 21 July 2017; Accepted: 07 August 2017; Published: 14 August 2017. We are grateful to Dr. Judith Frydman and Dr. Koning Shen for providing the HTTx1 constructs. Conflict of Interest statement. None declared. Funding: NINDS grant R01 NS074374 awarded to AK and PHP, and R21 NS098323 to DCL.
Funders:
Funding AgencyGrant Number
NIHR01 NS074374
NIHR21 NS098323
Issue or Number:21
Record Number:CaltechAUTHORS:20171009-124506815
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171009-124506815
Official Citation:Ali Khoshnan, Adam Sabbaugh, Barbara Calamini, Steven A Marinero, Denise E Dunn, Jung Hyun Yoo, Jan Ko, Donald C Lo, Paul H Patterson; IKKβ and mutant huntingtin interactions regulate the expression of IL-34: implications for microglial-mediated neurodegeneration in HD, Human Molecular Genetics, Volume 26, Issue 21, 1 November 2017, Pages 4267–4277, https://doi.org/10.1093/hmg/ddx315
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:82213
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Oct 2017 21:19
Last Modified:03 Oct 2019 18:52

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