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Keywords :
Amino Acid Sequence; Animals; Base Sequence; Binding Sites; Brain/metabolism; Cell Death; Cells, Cultured; DNA Mutational Analysis; Female; Gene Expression Regulation; Humans; Male; Membrane Potentials; Mice; Middle Aged; Mitochondria/metabolism/ultrastructure; Mitochondrial Proteins; Models, Molecular; Molecular Sequence Data; Parkinson Disease/genetics/metabolism/pathology; Point Mutation; Sequence Homology, Amino Acid; Serine Endopeptidases/genetics/metabolism; Transfection
Abstract :
[en] 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.
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