Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease. Academic Article uri icon

Overview

MeSH

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Apoptosis
  • Astrocytes
  • Basal Ganglia
  • Calcium
  • Cell Death
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Knockout
  • Microglia
  • Mitochondria
  • Substantia Nigra
  • Tyrosine 3-Monooxygenase
  • alpha-Synuclein

MeSH Major

  • Cyclophilins
  • Dopaminergic Neurons
  • MPTP Poisoning
  • Mitochondrial Membrane Transport Proteins

abstract

  • 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. 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. Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.

publication date

  • May 1, 2012

has subject area

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Apoptosis
  • Astrocytes
  • Basal Ganglia
  • Calcium
  • Cell Death
  • Cyclophilins
  • Disease Models, Animal
  • Dopaminergic Neurons
  • Humans
  • MPTP Poisoning
  • Mice
  • Mice, Knockout
  • Microglia
  • Mitochondria
  • Mitochondrial Membrane Transport Proteins
  • Substantia Nigra
  • Tyrosine 3-Monooxygenase
  • alpha-Synuclein

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3292750

Digital Object Identifier (DOI)

  • 10.1089/ars.2010.3849

PubMed ID

  • 21529244

Additional Document Info

start page

  • 855

end page

  • 868

volume

  • 16

number

  • 9