title: Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2.
abstract: The protease HtrA2 has a protective role inside mitochondria, but promotes apoptosis under stress. We previously identified the G399S HtrA2 mutation in Parkinson's disease (PD) patients and reported mitochondrial dysfunction in vitro. Mitochondrial dysfunction is a common feature of PD and related to neurodegeneration. Complete loss of HtrA2 has been shown to cause neurodegeneration in mice. However, the full impact of HtrA2 overexpression or the G399S mutation is still to be determined in vivo. Here, we report the first HtrA2 G399S transgenic mouse model. Our data suggest that the mutation has a dominant-negative effect. We also describe a toxic effect of wild-type (WT) HtrA2 overexpression. Only low overexpression of the G399S mutation allowed viable animals and we suggest that the mutant protein is likely unstable. This is accompanied by reduced mitochondrial respiratory capacity and sensitivity to apoptotic cell death. Mice overexpressing WT HtrA2 were viable, yet these animals have inhibited mitochondrial respiration and significant induction of apoptosis in the brain leading to motor dysfunction, highlighting the opposing roles of HtrA2. Our data further underscore the importance of HtrA2 as a key mediator of mitochondrial function and its fine regulatory role in cell fate. The location and abundance of HtrA2 is tightly controlled and, therefore, human mutations leading to gain- or loss of function could provide significant risk for PD-related neurodegeneration.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Casadei
authors.affiliation: Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany, Functional Neurogenomics Laboratory, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and, Centre for Integrative Neuroscience (CIN), University of Tübingen, Otfried-Mueller-Strasse 27, Tübingen 72076, Germany, The German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Poonam
authors.initials: P
authors.lastname: Sood
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Strasse. 4, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulrich
authors.affiliation: Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Fallier-Becker
authors.affiliation: Functional Neurogenomics Laboratory, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and, Centre for Integrative Neuroscience (CIN), University of Tübingen, Otfried-Mueller-Strasse 27, Tübingen 72076, Germany, The German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kieper
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstraße 150, Bochum, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Helling
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstraße 150, Bochum, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: May
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 av. des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg.
authors.forename: Enrico
authors.initials: E
authors.lastname: Glaab
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstraße 150, Bochum, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstraße 150, Bochum, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Strasse. 4, Tübingen, Germany.
authors.forename: Doron
authors.initials: D
authors.lastname: Rapaport
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany, Core Facility Transgenic Animals, University of Tübingen, Tübingen, Germany and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ott
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Functional Neurogenomics Laboratory, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and, Centre for Integrative Neuroscience (CIN), University of Tübingen, Otfried-Mueller-Strasse 27, Tübingen 72076, Germany, The German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 av. des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg.
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Functional Neurogenomics Laboratory, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and, Centre for Integrative Neuroscience (CIN), University of Tübingen, Otfried-Mueller-Strasse 27, Tübingen 72076, Germany, The German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany, julia.fitzgerald@uni-tuebingen.de rejko.krueger@uni.lu.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019069:Cell Respiration; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse