期刊
CELL DEATH AND DIFFERENTIATION
卷 17, 期 2, 页码 324-335出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.127
关键词
excitotoxicity; exon-1 mouse models; FoxO1; GSK3 beta; human samples; huntingtin
资金
- Fondo de Investigaciones Sanitarias [PI071183, RD06/0010/0006]
- Ministerio de Educacion y Ciencia [SAF2008-04360]
- Fundacio La Maratode TV3
- Fundacao para a Ciencia e Tecnologia, Portugal [SFRH/BPD/28252/2006]
- Ministerio de Educacion y Ciencia, Spain
- Fondo de Investigaciones Sanitarias
- Fundacio La Caixa, Spain
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/28252/2006] Funding Source: FCT
Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh(Q111/Q111) mouse striatum and STHdh(Q111/Q111) cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF +/-, R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing. Cell Death and Differentiation (2010) 17, 324-335; doi:10.1038/cdd.2009.127; published online 11 September 2009
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