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Updated: Mar 29, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2
Nicolas Casadei1, Poonam Sood2, Thomas Ulrich3
1Institute of Medical Genetics and Applied Genomics, University of Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany.
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.
Insights
The HtrA2 G399S mutation linked to Parkinson's disease causes mitochondrial dysfunction and neurodegeneration in mice. Overexpression of wild-type HtrA2 also impairs mitochondrial respiration and induces brain apoptosis, leading to motor deficits.
Area of Science:
- Mitochondrial biology
- Neuroscience
- Genetics
Background:
- HtrA2 protease plays a dual role in mitochondria, offering protection but promoting apoptosis under stress.
- Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD) and linked to neurodegeneration.
- The HtrA2 G399S mutation was previously identified in PD patients, with in vitro studies indicating mitochondrial dysfunction.
Purpose of the Study:
- To investigate the in vivo impact of the HtrA2 G399S mutation and wild-type HtrA2 overexpression.
- To establish the first transgenic mouse model for the HtrA2 G399S mutation.
- To elucidate the role of HtrA2 in mitochondrial function and neurodegeneration relevant to PD.
Main Methods:
- Generation of HtrA2 G399S transgenic mouse model.
- Assessment of animal viability and protein stability.
- Analysis of mitochondrial respiratory capacity and apoptosis induction.
- Evaluation of motor function in transgenic mice.
Main Results:
- The HtrA2 G399S mutation exhibits a dominant-negative effect and the mutant protein appears unstable, with only low overexpression yielding viable animals.
- Both G399S mutant and wild-type HtrA2 overexpression lead to reduced mitochondrial respiratory capacity and increased sensitivity to apoptosis.
- Mice overexpressing wild-type HtrA2 displayed inhibited mitochondrial respiration, significant brain apoptosis, and motor dysfunction.
Conclusions:
- HtrA2's location and abundance are critical for its function; alterations can significantly increase PD risk.
- HtrA2 is a key regulator of mitochondrial function and cellular fate, with its dysregulation contributing to neurodegeneration.
- The HtrA2 G399S mutation and wild-type HtrA2 overexpression have detrimental effects on mitochondrial health and neuronal function, underscoring HtrA2's complex role in PD pathogenesis.
