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Neurobiol Aging. 2014 May;35(5):1132-52. doi: 10.1016/j.neurobiolaging.2013.11.008. Epub 2013 Nov 16.

Mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice.

Author information

1
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: martinl@jhmi.edu.
2
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Abstract

Parkinson's disease (PD) is a movement disorder caused by neurodegeneration in neocortex, substantia nigra and brainstem, and synucleinopathy. Some inherited PD is caused by mutations in α-synuclein (αSyn), and inherited and idiopathic PD is associated with mitochondrial perturbations. However, the mechanisms of pathogenesis are unresolved. We characterized a human αSyn transgenic mouse model and tested the hypothesis that the mitochondrial permeability transition pore (mPTP) is involved in the disease mechanisms. C57BL/6 mice expressing human A53T-mutant αSyn driven by a thymic antigen-1 promoter develop a severe, age-related, fatal movement disorder involving ataxia, rigidity, and postural instability. These mice develop synucleinopathy and neocortical, substantia nigra, and cerebello-rubro-thalamic degeneration involving mitochondriopathy and apoptotic and non-apoptotic neurodegeneration. Interneurons undergo apoptotic degeneration in young mice. Mutant αSyn associated with dysmorphic neuronal mitochondria and bound voltage-dependent anion channels. Genetic ablation of cyclophilin D, an mPTP modulator, delayed disease onset, and extended lifespans of mutant αSyn mice. Thus, mutant αSyn transgenic mice on a C57BL/6 background develop PD-like phenotypes, and the mPTP is involved in their disease mechanisms.

KEYWORDS:

Adenine nucleotide translocase; Cerebellum; Interneuron; Porin; Ppif; Voltage-dependent anion channel 1

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