BH3-only proteins Bid and Bim(EL) are differentially involved in neuronal dysfunction in mouse models of Huntington's disease.
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 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.
García-Martínez
Juan M
JM
Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
Pérez-Navarro
Esther
E
Xifró
Xavier
X
Canals
Josep M
JM
Díaz-Hernández
Miguel
M
Trioulier
Yael
Y
Brouillet
Emmanuel
E
Lucas
José J
JJ
Alberch
Jordi
J
D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002540:Cerebral Cortex / Q000473:pathology; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology; D014162:Transfection / Q000379:methods
D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D019208:Brain-Derived Neurotrophic Factor; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D053148:Caspase 3