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Partial depletion of CREB-binding protein reduces life expectancy in a mouse model of Huntington disease.

Authors: Klevytska, Alexandra M  Tebbenkamp, Andrew T N  Savonenko, Alena V  Borchelt, David R 
Citation: Klevytska AM, etal., J Neuropathol Exp Neurol. 2010 Apr;69(4):396-404. doi: 10.1097/NEN.0b013e3181d6c436.
Pubmed: (View Article at PubMed) PMID:20448484
DOI: Full-text: DOI:10.1097/NEN.0b013e3181d6c436

Previous studies have reported that mutant huntingtin (htt) interferes with cyclic AMP response element binding protein binding protein (CBP)-mediated transcription, possibly by inhibiting the acetylation of histones. In Drosophila models that express fragments of mutant htt, histone deacetylase inhibitors reverse deficits in histone acetylation, rescue photoreceptor degeneration, and prolong their survival. These compounds also improve motor deficits in a transgenic mouse model of Huntington disease (HD). To determine whether endogenous CBP depletion contributes to HD pathogenesis, we crossed HD-N171-82Q transgenic mice with mice harboring a disrupted CBP gene and produced mice with partial (50%) depletion of CBP. This reduction of CBP levels decreased the life expectancy of the HD-N171-82Q Line 6 mouse model. The loss of CBP had no obvious impact on the severity of motor impairment, degeneration of the striatum, mutant htt inclusion formation, or global levels of acetylated histones H3 or H4 in brain. In cell models, we confirmed that mutant htt inclusions recruit human CBP but found no evidence for interactions between soluble forms of mutant htt and CBP. Although we identified no neurological explanation for the decreased life expectancy of HD-N171-82Q mice with partial depletion of CBP, the data are consistent with the notion that CBP function mitigates mutant htt toxicity by a currently unidentified mechanism.


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RGD Object Information
RGD ID: 13432094
Created: 2017-09-19
Species: All species
Last Modified: 2017-09-19
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.