title: Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease.
abstract: OBJECTIVE
  Mitochondrial damage due to Ca(2+) overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca(2+) threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD.
  
  
  RESULTS
  We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms.
  
  
  METHODS
  Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity.
  
  
  CONCLUSIONS
  Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.forename: Rebecca
authors.initials: R
authors.lastname: Banerjee
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Starkova
authors.forename: Steven F
authors.initials: SF
authors.lastname: Zhang
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wille
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Lorenzo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ho
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Anatoly
authors.initials: A
authors.lastname: Starkov
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001253:Astrocytes / Q000187:drug effects; D001479:Basal Ganglia / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D000083162:Mitochondrial Permeability Transition Pore; D013378:Substantia Nigra / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D021983:Cyclophilins; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium