Partial depletion of CREB-binding protein reduces life expectancy in a mouse model of Huntington disease.
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.
Klevytska
Alexandra M
AM
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Tebbenkamp
Andrew T N
AT
Savonenko
Alena V
AV
Borchelt
David R
DR
D000818:Animals; D002461:Cell Line, Transformed; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency*; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins