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RTP801 Is Involved in Mutant Huntingtin-Induced Cell Death

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Abstract

RTP801 expression is induced by cellular stress and has a pro-apoptotic function in non-proliferating differentiated cells such as neurons. In several neurodegenerative disorders, including Parkinson’s disease and Alzheimer’s disease, elevated levels of RTP801 have been observed, which suggests a role for RTP801 in neuronal death. Neuronal death is also a pathological hallmark in Huntington’s disease (HD), an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Currently, the exact mechanisms underlying mutant huntingtin (mhtt)-induced toxicity are still unclear. Here, we investigated whether RTP801 is involved in (mhtt)-induced cell death. Ectopic exon-1 mhtt elevated RTP801 mRNA and protein levels in nerve growth factor (NGF)-differentiated PC12 cells and in rat primary cortical neurons. In neuronal PC12 cells, mhtt also contributed to RTP801 protein elevation by reducing its proteasomal degradation rate, in addition to promoting RTP801 gene expression. Interestingly, silencing RTP801 expression with short hairpin RNAs (shRNAs) blocked mhtt-induced cell death in NGF-differentiated PC12 cells. However, RTP801 protein levels were not altered in the striatum of HdhQ7/Q111 and R6/1 mice, two HD models that display motor deficits but not neuronal death. Importantly, RTP801 protein levels were elevated in both neural telencephalic progenitors differentiated from HD patient-derived induced pluripotent stem cells and in the putamen and cerebellum of human HD postmortem brains. Taken together, our results suggest that RTP801 is a novel downstream effector of mhtt-induced toxicity and that it may be relevant to the human disease.

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Acknowledgments

The authors thank Dr. M. MacDonald (Massachusetts General Hospital, Boston, Massachusetts, USA) for the HdhQ7/Q111 mice, 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, Dr. G.M. Lawless (Cure HD Initiative, Reagent Resource Bank of the Hereditary Disease Foundation, New York, NY) for exon-1-mhtt-expressing plasmids and Dr. C. Svendsen (Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA) for the iPS cells. iPSCs were obtained and characterized in the context of the HD-iPSC Consortium supported by the NINDS and CHDI Foundation, USA. M. MacDonald, C.S., PS, MS, NA, and JMC are members of the HD iPSC consortium. We also thank Ana López, Maria Teresa Muñoz, and Georgina Bombau for technical assistance and Dr. Teresa Rodrigo and the staff of the animal care facility (Facultat de Psicologia, Universitat de Barcelona) for their help. We thank Dr. Sílvia Ginés for helpful discussion. Financial support was obtained from the Ministerio de Economia y Competitividad (grants SAF2010-21058 and SAF2013-45888R to C.M., SAF2012-37417 to J.M.C., and SAF2011-29507 to J.A.), projects integrated in the Plan Nacional de I + D + I y cofinanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER; grants PI13/01250 to E.P.-N. and RETICS RD12/0019/0002 to J.M.C.), the European Commission with a Marie Curie International Reintegration Grant (PIRG08-GA-2010-276957), Spain, CHDI Foundation, USA (grants A-4528 to N.A. and A-7332 to J.M.C.), and funds obtained via the crowdfunding platform Goteo.org, sponsored by “Mememtum: early detection of neurological disorders” and Portal d’Avall SL. to C.M.

Conflict of Interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain

    Núria Martín-Flores, Joan Romaní-Aumedes, Mercè Canal & Cristina Malagelada

  2. Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain

    Laura Rué, Phil Sanders, Marco Straccia, Jordi Alberch, Josep M. Canals & Esther Pérez-Navarro

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

    Laura Rué, Phil Sanders, Marco Straccia, Jordi Alberch, Josep M. Canals & Esther Pérez-Navarro

  4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Laura Rué, Phil Sanders, Marco Straccia, Jordi Alberch, Josep M. Canals & Esther Pérez-Navarro

  5. Divisions of Pathophysiology & Repair and Neuroscience, School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK

    Nicholas D. Allen

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  1. Núria Martín-Flores
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Correspondence to Esther Pérez-Navarro or Cristina Malagelada.

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Martín-Flores, N., Romaní-Aumedes, J., Rué, L. et al. RTP801 Is Involved in Mutant Huntingtin-Induced Cell Death. Mol Neurobiol 53, 2857–2868 (2016). https://doi.org/10.1007/s12035-015-9166-6

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