title: RTP801 Is Involved in Mutant Huntingtin-Induced Cell Death.
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 Hdh(Q7/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.
authors: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.
authors: Núria
authors: N
authors: Martín-Flores
authors: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.
authors: Joan
authors: J
authors: Romaní-Aumedes
authors: Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Laura
authors: L
authors: Rué
authors: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.
authors: Mercè
authors: M
authors: Canal
authors: Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Phil
authors: P
authors: Sanders
authors: Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Marco
authors: http://orcid.org/0000-0003-3903-4163
authors: M
authors: Straccia
authors: Divisions of Pathophysiology & Repair and Neuroscience, School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK.
authors: Nicholas D
authors: ND
authors: Allen
authors: Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Jordi
authors: J
authors: Alberch
authors: Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Josep M
authors: JM
authors: Canals
authors: Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain. estherperez@ub.edu.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Catalonia, Spain. estherperez@ub.edu.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. estherperez@ub.edu.
authors: Esther
authors: E
authors: Pérez-Navarro
authors: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain. crismalagelada@gmail.com.
authors: Cristina
authors: http://orcid.org/0000-0001-7185-436X
authors: C
authors: Malagelada
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein / Q000633:toxicity*; D006816:Huntington Disease / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D050505:Mutant Proteins / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C000632146:Ddit4 protein, rat; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors
keywords: Exon-1 mutant huntingtin; HdHQ7/Q111 mice; Neuron death; PC12 cells; Putamen; R6/1 mice; RTP801; Striatum