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A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease
Karsten M Strauss1, L Miguel Martins, Helene Plun-Favreau
1Center of Neurology and Hertie-Institute for Clinical Brain Research, Leicester, UK.
Abstract:
Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.
Insights
Mutations in the Omi/HtrA2 gene were identified in Parkinson's disease patients, leading to defective protease activity and mitochondrial dysfunction. These findings link mitochondrial issues to neurodegeneration in Parkinson's disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Targeted disruption of Omi/HtrA2 in mice causes neurodegeneration and a parkinsonian phenotype.
- Parkinson's disease (PD) is a neurodegenerative disorder with complex genetic and molecular underpinnings.
Purpose of the Study:
- To screen the Omi/HtrA2 gene for mutations in German Parkinson's disease patients.
- To investigate the functional consequences of identified Omi/HtrA2 mutations on protease activity and mitochondrial function.
Main Methods:
- Candidate gene mutation screening of Omi/HtrA2 in PD patients and healthy controls.
- Functional analysis of mutations using protease activity assays and stably transfected cell lines.
- Immunohistochemistry and assessment of mitochondrial morphology and cell death susceptibility.
Main Results:
- A novel heterozygous G399S mutation in Omi/HtrA2 was identified in four PD patients and absent in controls.
- A novel A141S polymorphism was associated with PD (P<0.05).
- Both mutations impaired Omi/HtrA2 protease activity, induced mitochondrial dysfunction, altered mitochondrial morphology, and increased susceptibility to cell death.
Conclusions:
- The study provides a novel link between Omi/HtrA2 mutations, mitochondrial dysfunction, and neurodegeneration in Parkinson's disease.
- Omi/HtrA2 mutations may contribute to PD pathogenesis through impaired mitochondrial function and increased cellular vulnerability.
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