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Early Down-Regulation of PKCδ as a Pro-Survival Mechanism in Huntington’s Disease

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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 HdhQ111/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.

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Acknowledgments

The authors thank Dr. M MacDonald (Massachusetts General Hospital, Boston, MA, USA) for the STHdhQ7/Q7 cell line and HdhQ7/Q111 mice, Dr. J. J Lucas (Center for Molecular Biology Severo Ochoa, Madrid, Spain) for the generous gift of the N-WThtt-CFP and N-mhtt-CFP plasmids, Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS (Barcelona, Spain) and Institute of Neuropathology (Hospital de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain) for human tissue samples. We also thank Ana López and Maria Teresa Muñoz for technical assistance, and Dr. Teresa Rodrigo, Dr. Amèrica Jiménez, and the staff of the animal care facility (Facultat de Psicologia and Facultat de Medicina, Universitat de Barcelona) for their help. Financial support was obtained from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, (grant numbers PI071183, PI10/01072 to E.P.-N., RETICS: RD06/0010/0006), the Ministerio de Educación y Ciencia (grant SAF2011-29507 to J.A.), and Generalitat de Catalunya (Grant number 2009SGR-00326 to J.A.). L.R is a fellow of Ministerio de Educación y Ciencia, Spain (grant number AP2007-01066).

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The authors declare no competing financial interests.

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Authors and Affiliations

  1. Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, Barcelona, 08036, Spain

    Laura Rué, Rafael Alcalá-Vida, Graciela López-Soop, Jordi Creus-Muncunill, Jordi Alberch & Esther Pérez-Navarro

  2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain

    Laura Rué, Rafael Alcalá-Vida, Graciela López-Soop, Jordi Creus-Muncunill, Jordi Alberch & Esther Pérez-Navarro

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    Laura Rué, Rafael Alcalá-Vida, Graciela López-Soop, Jordi Creus-Muncunill, Jordi Alberch & Esther Pérez-Navarro

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  1. Laura Rué
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Correspondence to Esther Pérez-Navarro.

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Rué, L., Alcalá-Vida, R., López-Soop, G. et al. Early Down-Regulation of PKCδ as a Pro-Survival Mechanism in Huntington’s Disease. Neuromol Med 16, 25–37 (2014). https://doi.org/10.1007/s12017-013-8248-8

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