TY - JOUR
T1 - Partial depletion of CREB-binding protein reduces life expectancy in a mouse model of Huntington disease
AU - Klevytska, Alexandra M.
AU - Tebbenkamp, Andrew T.N.
AU - Savonenko, Alena V.
AU - Borchelt, David R.
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
KW - CREB binding protein
KW - Huntingtin
KW - Knockout mice
KW - Neurodegeneration
KW - Transgenic mice
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U2 - 10.1097/NEN.0b013e3181d6c436
DO - 10.1097/NEN.0b013e3181d6c436
M3 - Article
C2 - 20448484
AN - SCOPUS:77950794366
SN - 0022-3069
VL - 69
SP - 396
EP - 404
JO - Journal of neuropathology and experimental neurology
JF - Journal of neuropathology and experimental neurology
IS - 4
ER -