title: Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease.
abstract: Mutations in the PARK2 gene are associated with an autosomal recessive form of juvenile parkinsonism (AR-JP). These mutations affect parkin solubility and impair its E3 ligase activity, leading to a toxic accumulation of proteins within susceptible neurons that results in a slow but progressive neuronal degeneration and cell death. Here, we report that RTP801/REDD1, a pro-apoptotic negative regulator of survival kinases mTOR and Akt, is one of such parkin substrates. We observed that parkin knockdown elevated RTP801 in sympathetic neurons and neuronal PC12 cells, whereas ectopic parkin enhanced RTP801 poly-ubiquitination and proteasomal degradation. In parkin knockout mouse brains and in human fibroblasts from AR-JP patients with parkin mutations, RTP801 levels were elevated. Moreover, in human postmortem PD brains with mutated parkin, nigral neurons were highly positive for RTP801. Further consistent with the idea that RTP801 is a substrate for parkin, the two endogenous proteins interacted in reciprocal co-immunoprecipitates of cell lysates. A potential physiological role for parkin-mediated RTP801 degradation is indicated by observations that parkin protects neuronal cells from death caused by RTP801 overexpression by mediating its degradation, whereas parkin knockdown exacerbates such death. Similarly, parkin knockdown enhanced RTP801 induction in neuronal cells exposed to the Parkinson's disease mimetic 6-hydroxydopamine and increased sensitivity to this toxin. This response to parkin loss of function appeared to be mediated by RTP801 as it was abolished by RTP801 knockdown. Taken together these results indicate that RTP801 is a novel parkin substrate that may contribute to neurodegeneration caused by loss of parkin expression or activity.
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Romaní-Aumedes
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Canal
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Martín-Flores
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Pérez-Fernández
authors.affiliation: Department of Animal Physiology, Faculty for Biology, Ruhr University, Bochum, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wewering
authors.affiliation: 1] Laboratory of Neurodegenerative Disorders and Department of Neurology, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain [2] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Fernández-Santiago
authors.affiliation: 1] Laboratory of Neurodegenerative Disorders and Department of Neurology, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain [2] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ezquerra
authors.affiliation: Laboratory of Neurodegenerative Disorders and Department of Neurology, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pont-Sunyer
authors.affiliation: 1] Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain [2] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Lafuente
authors.affiliation: 1] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain [2] Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Alberch
authors.affiliation: Department of Animal Physiology, Faculty for Biology, Ruhr University, Bochum, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Luebbert
authors.affiliation: 1] Laboratory of Neurodegenerative Disorders and Department of Neurology, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain [2] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Tolosa
authors.affiliation: Department of Neurology Columbia University, New York, NY, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Levy
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Greene
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Malagelada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C000632146:Ddit4 protein, rat; D007976:Leupeptins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D016627:Oxidopamine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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