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Partial depletion of CREB-binding protein reduces life expectancy in a mouse model of Huntington disease.
- Source :
-
Journal of neuropathology and experimental neurology [J Neuropathol Exp Neurol] 2010 Apr; Vol. 69 (4), pp. 396-404. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Animals
Cell Line, Transformed
Disease Models, Animal
Humans
Huntington Disease genetics
Male
Mice
Mice, Transgenic
Mutation genetics
Nerve Tissue Proteins metabolism
Serotonin Plasma Membrane Transport Proteins genetics
Transfection
Trinucleotide Repeat Expansion genetics
Cyclic AMP Response Element-Binding Protein deficiency
Huntington Disease physiopathology
Longevity genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1554-6578
- Volume :
- 69
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of neuropathology and experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 20448484
- Full Text :
- https://doi.org/10.1097/NEN.0b013e3181d6c436