title: Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.
abstract: BACKGROUND
  Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.
  
  
  RESULTS
  Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.
  
  
  CONCLUSIONS
  Thus, aging Pink1(-/-) mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
authors.affiliation: Department of Neurology, University Medical School, Frankfurt am Main, Germany.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.forename: Filomena
authors.initials: F
authors.lastname: Ricciardi
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurz
authors.forename: Mekhman
authors.initials: M
authors.lastname: Azizov
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Hoepken
authors.forename: Dorothea
authors.initials: D
authors.lastname: Becker
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Voos
authors.forename: Kristina
authors.initials: K
authors.lastname: Leuner
authors.forename: Walter E
authors.initials: WE
authors.lastname: Müller
authors.forename: Alexei P
authors.initials: AP
authors.lastname: Kudin
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Annabelle
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Jochen
authors.initials: J
authors.lastname: Roeper
authors.forename: Dirk
authors.initials: D
authors.lastname: Wenzel
authors.forename: Marina
authors.initials: M
authors.lastname: Jendrach
authors.forename: Moisés
authors.initials: M
authors.lastname: García-Arencíbia
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.forename: Leslie
authors.initials: L
authors.lastname: Huber
authors.forename: Hermann
authors.initials: H
authors.lastname: Rohrer
authors.forename: Miguel
authors.initials: M
authors.lastname: Barrera
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Reichert
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
authors.forename: Amy
authors.initials: A
authors.lastname: Chen
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics; D051844:alpha-Synuclein / Q000096:biosynthesis; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000255:Adenosine Triphosphate; D011494:Protein Kinases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase