Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2
| Autor: | Enrico Glaab, Thomas Ott, Hartwig Wolburg, Stefan Helling, Julia C. Fitzgerald, Rejko Krüger, Caroline May, Jing Chen, Katrin Marcus, Nicolas Casadei, Poonam Sood, Silke Nuber, Olaf Riess, Petra Fallier-Becker, Doron Rapaport, Thomas Ulrich, Nicole Kieper |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Mutant Gene Dosage HTRA2 protein human Apoptosis genetics [Serine Endopeptidases] Mitochondrion medicine.disease_cause pathology [Mitochondria] Mice 0302 clinical medicine pathology [Brain] genetics [Parkinson Disease] Mutant protein pathology [Neurons] Genetics (clinical) Neurons Mutation 0303 health sciences Neurodegeneration Serine Endopeptidases Brain Parkinson Disease General Medicine High-Temperature Requirement A Serine Peptidase 2 Cell biology Mitochondria Phenotype metabolism [Neurons] genetics [Mitochondrial Proteins] Female Genetically modified mouse Cell Respiration metabolism [Parkinson Disease] Mice Transgenic genetics [Electron Transport Chain Complex Proteins] Biology Motor Activity metabolism [Mitochondrial Proteins] Mitochondrial Proteins 03 medical and health sciences metabolism [Serine Endopeptidases] ddc:570 medicine Genetics Animals Humans metabolism [Electron Transport Chain Complex Proteins] Molecular Biology 030304 developmental biology Wild type Htra2 protein mouse metabolism [Mitochondria] medicine.disease Molecular biology pathology [Parkinson Disease] Disease Models Animal 030104 developmental biology Electron Transport Chain Complex Proteins Gene Expression Regulation metabolism [Brain] genetics [Mitochondria] 030217 neurology & neurosurgery |
| Zdroj: | Human molecular genetics 25(24), ddw353 (2016). doi:10.1093/hmg/ddw353 Human molecular genetics 25(3), 459-471 (2015). doi:10.1093/hmg/ddv485 Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddw353 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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