Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage.
Mutations in the gene encoding alpha-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 (hm(2)asyn) 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.
Stichel
Christine C
CC
Biofrontera Bioscience GmbH, D-51377 Leverkusen, Germany. c.stichel-gunkel@biofrontera.com
Zhu
Xin-Ran
XR
Bader
Verian
V
Linnartz
Bettina
B
Schmidt
Saskia
S
Lübbert
Hermann
H
D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure; D008931:Mitochondria, Muscle / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010300:Parkinson Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein