BH3-only proteins bid and BimEL are differentially involved in neuronal dysfunction in mouse models of Huntington's disease
BH3-only proteins bid and BimEL are differentially involved in neuronal dysfunction in mouse models of Huntington's disease
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DOI：
10.1002/jnr.21258
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发表时间：
2007-09-01
影响因子：
4.2
通讯作者：
Albech, Jordi
中科院分区：
文献类型：
--
作者：
Garcia-Martinez, Juan M.;Perez-Navarro, Esther;Albech, Jordi
细胞凋亡是一种由Bcl-2家族成员调控的细胞死亡机制，已被认为是导致亨廷顿病（HD）神经元丢失的机制之一。在这里，我们研究了Bcl-2家族蛋白在三种不同的HD小鼠模型与外显子1突变亨廷顿蛋白的调节：R6/1，R6/1：BDNF+/-，和泰特/HD 94，其中亨廷顿基因是由四环素诱导系统控制。我们的研究结果揭示了HD小鼠模型纹状体中仅BH 3蛋白Bid和Bim（EL）水平的增加，这取决于疾病的阶段。在16周龄时，Bid在R6/1和R6/1：BDNF+/-小鼠的纹状体中类似地增强，而Bim（EL）蛋白水平仅在R6/1：BDNF+/-小鼠中增强。相反，在疾病的后期，两种基因型显示Bid和Bim（EL）蛋白水平增加。此外，Bax、巴克、Bad、Bcl-2和Bcl-x（L）蛋白在分析的任何点中均未被修饰。我们接下来通过分析条件性泰特/HD 94小鼠来探索这种现象的潜在可逆性。转基因的组成型表达导致Bid和Bim（EL）蛋白水平增加，只有Bid蛋白在突变亨廷顿蛋白关闭后5个月恢复到野生型水平。总之，我们的研究结果表明，增强Bid蛋白水平代表了一个早期的机制与突变亨廷顿蛋白的连续表达，连同增强的Bim（EL），可能是一个记者的进展和严重程度的神经元功能障碍。(C)2007 Wiley-Liss，Inc.
Apoptosis, a cell death mechanism regulated by Bcl-2 family members, has been proposed as one of the mechanisms leading to neuronal loss in Huntington's disease (HD). Here we examined the regulation of Bcl-2 family proteins in three different mouse models of HD with exon 1 mutant huntingtin: the R6/1, the R6/1:BDNF+/-, and the Tet/HD94 in which the huntingtih transgene is controlled by the tetracycline-inducible system. Our results disclosed an increase in the levels of the BH3-only proteins Bid and Bim(EL) in the striatum of HD mouse models that was different depending on the stage of the disease. At 16 weeks of age, Bid was similarly enhanced in the striatum of R6/1 and R6/1:BDNF+/- mice, whereas Bim(EL) protein levels were enhanced only in R6/1:BDNF+/- mice. In contrast, at later stages of the disease, both genotypes displayed increased levels of Bid and Bim(EL) proteins. Furthermore, Bax, Bak, Bad, Bcl-2, and Bcl-x(L) proteins were not modified in any of the points analyzed. We next explored the potential reversibility of this phenomenon by analyzing conditional Tet/HD94 mice. Constitutive expression of the transgene resulted in increased levels of Bid and Bim(EL) proteins, and only the Bid protein returned to wild-type levels 5 months after mutant huntingtin shutdown. In conclusion, our results show that enhanced Bid protein levels represent an early mechanism linked to the continuous expression of mutant huntingtin that, together with enhanced Bim(EL), may be a reporter of the progress and severity of neuronal dysfunction. (C) 2007 Wiley-Liss, Inc.