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.
Original language | English (US) |
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Pages (from-to) | 1132-1152 |
Number of pages | 21 |
Journal | Neurobiology of aging |
Volume | 35 |
Issue number | 5 |
DOIs | |
State | Published - May 2014 |
Keywords
- Adenine nucleotide translocase
- Cerebellum
- Interneuron
- Porin
- Ppif
- Voltage-dependent anion channel 1
ASJC Scopus subject areas
- Neuroscience(all)
- Aging
- Clinical Neurology
- Developmental Biology
- Geriatrics and Gerontology