Khoshnan, Ali and Ko, Jan and Tescu, Simona and Brundin, Patrick and Patterson, Paul H. (2009) IKKα and IKKβ Regulation of DNA Damage-Induced Cleavage of Huntingtin. PLoS ONE, 4 (6). Art. No. e5768. ISSN 1932-6203 http://resolver.caltech.edu/CaltechAUTHORS:20100121-100806538
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Background: Proteolysis of huntingtin (Htt) plays a key role in the pathogenesis of Huntington's disease (HD). However, the environmental cues and signaling pathways that regulate Htt proteolysis are poorly understood. One stimulus may be the DNA damage that accumulates in neurons over time, and the subsequent activation of signaling pathways such as those regulated by IκB kinase (IKK), which can influence neurodegeneration in HD. Methodology/Principal Findings: We asked whether DNA damage induces the proteolysis of Htt and if activation of IKK plays a role. We report that treatment of neurons with the DNA damaging agent etoposide or γ-irradiation promotes cleavage of wild type (WT) and mutant Htt, generating N-terminal fragments of 80–90 kDa. This event requires IKKβ and is suppressed by IKKα. Elevated levels of IKKα, or inhibition of IKKβ expression by a specific small hairpin RNA (shRNA) or its activity by sodium salicylate, prevents Htt proteolysis and increases neuronal resistance to DNA damage. Moreover, IKKβ phosphorylates the anti-apoptotic protein Bcl-xL, a modification known to reduce Bcl-xL levels, and activates caspases that can cleave Htt. When IKKβ expression is blocked, etoposide treatment does not decrease Bcl-xL and activation of caspases is diminished. Similar to silencing of IKKβ, increasing the level of Bcl-xL in neurons prevents etoposide-induced caspase activation and Htt proteolysis. Conclusions/Significance: These results indicate that DNA damage triggers cleavage of Htt and identify IKKβ as a prominent regulator. Moreover, IKKβ-dependent reduction of Bcl-xL is important in this process. Thus, inhibition of IKKβ may promote neuronal survival in HD as well as other DNA damage-induced neurodegenerative disorders.
|Additional Information:||© 2009 Khoshnan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received February 12, 2009; Accepted May 8, 2009; Published June 2, 2009. Funding: NINDS 5RO1NS55298 and Hereditary Disease Foundation (HDF)(www.hdfoundation.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank David Baltimore for providing lentiviral plasmids, Tularik, Inc. for IKKa cDNA and Marcy Macdonald for mouse striatal precursor cells. We are grateful to Haick Issaian for his help on the c-irradiation experiments. Author Contributions: Conceived and designed the experiments: AK. Performed the experiments: AK ST. Analyzed the data: AK JK PHP. Contributed reagents/materials/ analysis tools: PB. Wrote the paper: AK PHP.|
|Subject Keywords:||Neurological Disorders|
|Official Citation:||Khoshnan A, Ko J, Tescu S, Brundin P, Patterson PH (2009) IKKa and IKKb Regulation of DNA Damage-Induced Cleavage of Huntingtin. PLoS ONE 4(6): e5768. doi:10.1371/journal.pone.0005768|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||25 Jan 2010 20:00|
|Last Modified:||26 Dec 2012 11:43|
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