SAHA Decreases HDAC 2 and 4 Levels In Vivo and Improves Molecular Phenotypes in the R6/2 Mouse Model of Huntington's Disease

被引:130
作者
Mielcarek, Michal [1 ]
Benn, Caroline L. [2 ]
Franklin, Sophie A. [1 ]
Smith, Donna L. [1 ]
Woodman, Ben [1 ]
Marks, Paul A. [3 ]
Bates, Gillian P. [1 ]
机构
[1] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England
[2] Pfizer Inc, Neusentis, Cambridge, England
[3] Mem Sloan Kettering Canc Ctr, Cell Biol Program, Sloan Kettering Inst Canc Res, New York, NY 10021 USA
关键词
HISTONE DEACETYLASE INHIBITORS; NEURONAL INTRANUCLEAR INCLUSIONS; SUBEROYLANILIDE HYDROXAMIC ACID; NEUROTROPHIC FACTOR; EXPRESSION; TRANSCRIPTION; PATHOGENESIS; UNDERLIES; TRIALS;
D O I
10.1371/journal.pone.0027746
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Huntington's disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Transcriptional dysregulation is a major molecular feature of HD, which significantly contributes to disease progression. Therefore, the development of histone deacetylase (HDAC) inhibitors as therapeutics for HD has been energetically pursued. Suberoylanilide hydroxamic acid (SAHA) - a class I HDAC as well an HDAC6 inhibitor, improved motor impairment in the R6/2 mouse model of HD. Recently it has been found that SAHA can also promote the degradation of HDAC4 and possibly other class IIa HDACs at the protein level in various cancer cell lines. To elucidate whether SAHA is a potent modifier of HDAC protein levels in vivo, we performed two independent mouse trials. Both WT and R6/2 mice were chronically treated with SAHA and vehicle. We found that prolonged SAHA treatment causes the degradation of HDAC4 in cortex and brain stem, but not hippocampus, without affecting its transcript levels in vivo. Similarly, SAHA also decreased HDAC2 levels without modifying the expression of its mRNA. Consistent with our previous data, SAHA treatment diminishes Hdac7 transcript levels in both wild type and R6/2 brains and unexpectedly was found to decrease Hdac11 in R6/2 but not wild type. We investigated the effects of SAHA administration on well-characterised molecular readouts of disease progression. We found that SAHA reduces SDS-insoluble aggregate load in the cortex and brain stem but not in the hippocampus of the R6/2 brains, and that this was accompanied by restoration of Bdnf cortical transcript levels.
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页数:10
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