Human Molecular Genetics Advance Access originally published online on April 5, 2007
Human Molecular Genetics 2007 16(20):2377-2393; doi:10.1093/hmg/ddm083
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Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage
1 Biofrontera Bioscience GmbH, D-51377 Leverkusen, Germany, 2 Department of Animal Physiology, Ruhr-University of Bochum, D-44780 Bochum, Germany and 3 Biofrontera AG, D-51377 Leverkusen, Germany
* To whom correspondence should be addressed at: Animal Physiology, Biology, ND5/132 Ruhr-University Bochum, D-44780 Bochum, Germany. Tel: +49 2343225829; Fax: +49 2343214189; Email: c.stichel-gunkel{at}biofrontera.com
Received December 27, 2006; Revised February 7, 2007; Accepted March 26, 2007
Mutations in the gene encoding 
-synuclein (asyn) causes autosomal-dominant, in the parkin gene autosomal-recessive forms of Parkinson's disease (PD). The pathophysiology of PD is poorly understood, even though published evidence suggests a role for mitochondria in the pathogenesis. To gain insight into the influence of asyn and parkin on mitochondrial integrity and function, we have generated several mono-mutant mouse lines expressing doubly mutated human asyn (hm2asyn) under the control of two different promoters, or a targeted deletion of Parkin (Parkin-Exon3-knockout). Both mouse lines were crossed to generate the double-mutant. Here we compare the ultrastructure and functional properties of mitochondria in the substantia nigra (SN), the striatum, the cerebral cortex (Cx) and skeletal muscle of young (2–3 months) and aged (12–14 months) mono- and double-mutants mice. We observed severe genotype-, age- and region-dependent morphological alterations of mitochondria in neuronal somata. The number of structurally altered mitochondria was significantly increased in the SN of both double-mutants and in the Cx of one mono- and one double-mutant line. These alterations coincided with a reduced complex I capacity in the SN, but were neither accompanied by alterations in the number or the size of the mitochondria nor by leakage of cytochrome c, Smac/DIABLO or Omi/HtrA2. None of the transgenic animals developed any gross histopathological abnormalities or overt motor disabilities. Together our results provide compelling evidence that (i) both, asyn and parkin are relevant for mitochondrial integrity, (ii) the influence of these proteins on mitochondria are age- and tissue-specific and (iii) changes of mitochondrial morphology do not inevitably cause functional impairments.
The authors wish it to be known that, in their opinion, the first 3 authors should be regarded as joint First Authors.
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