BH3-only proteins Bid and BimEL are differentially involved in neuronal dysfunction in mouse models of Huntington's disease

• Published in: Journal of neuroscience research 2007-09, Vol.85 (12), p.2756-2769
• Main Authors: García-Martínez, Juan M., Pérez-Navarro, Esther, Xifró, Xavier, Canals, Josep M., Díaz-Hernández, Miguel, Trioulier, Yael, Brouillet, Emmanuel, Lucas, José J., Alberch, Jordi
• Format: Article
• Language: English
• Subjects: BDNF; HD94 mice; R6/1 mice; striatum
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.21258

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 huntingtin transgene is controlled by the tetracycline‐inducible system. Our results disclosed an increase in the levels of the BH3‐only proteins Bid and BimEL 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 BimEL 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 BimEL proteins. Furthermore, Bax, Bak, Bad, Bcl‐2, and Bcl‐xL 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 BimEL 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 BimEL, may be a reporter of the progress and severity of neuronal dysfunction. © 2007 Wiley‐Liss, Inc.