title: Early down-regulation of PKCδ as a pro-survival mechanism in Huntington's disease.
abstract: A balance between cell survival and apoptosis is crucial to avoid neurodegeneration. Here, we analyzed whether the pro-apoptotic protein PKCδ, and the pro-survival PKCα and βII, were dysregulated in the brain of R6/1 mouse model of Huntington's disease (HD). Protein levels of the three PKCs examined were reduced in all the brain regions analyzed being PKCδ the most affected isoform. Interestingly, PKCδ protein levels were also decreased in the striatum and cortex of R6/2 and Hdh(Q111/Q111) mice, and in the putamen of HD patients. Nuclear PKCδ induces apoptosis, but we detected reduced PKCδ in both cytoplasmic and nuclear enriched fractions from R6/1 mouse striatum, cortex and hippocampus. In addition, we show that phosphorylation and ubiquitination of PKCδ are increased in 30-week-old R6/1 mouse brain. All together these results suggest a pro-survival role of reduced PKCδ levels in response to mutant huntingtin-induced toxicity. In fact, we show that over-expression of PKCδ increases mutant huntingtin-induced cell death in vitro, whereas over-expression of a PKCδ dominant negative form or silencing of endogenous PKCδ partially blocks mutant huntingtin-induced cell death. Finally, we show that the analysis of lamin B protein levels could be a good marker of PKCδ activity, but it is not involved in PKCδ-mediated cell death in mutant huntingtin-expressing cells. In conclusion, our results suggest that neurons increase the degradation of PKCδ as a compensatory pro-survival mechanism in response to mutant huntingtin-induced toxicity that can help to understand why cell death appears late in the disease.
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, Barcelona, 08036, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rué
authors.forename: Rafael
authors.initials: R
authors.lastname: Alcalá-Vida
authors.forename: Graciela
authors.initials: G
authors.lastname: López-Soop
authors.forename: Jordi
authors.initials: J
authors.lastname: Creus-Muncunill
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
mesh_terms: D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology; D003342:Corpus Striatum / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000473:pathology; D034921:Lamin Type B / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000201:enzymology; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000032:analysis; D051571:Protein Kinase C-alpha / Q000032:analysis; D051745:Protein Kinase C-delta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011699:Putamen / Q000201:enzymology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D034921:Lamin Type B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta
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