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) |
|---|---|
| Pages (from-to) | 1132-1152 |
| Number of pages | 21 |
| Journal | Neurobiology of Aging |
| Volume | 35 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2014 |
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Keywords
- Adenine nucleotide translocase
- Cerebellum
- Interneuron
- Porin
- Ppif
- Voltage-dependent anion channel 1
ASJC Scopus subject areas
- Clinical Neurology
- Neuroscience(all)
- Aging
- Developmental Biology
- Geriatrics and Gerontology
Cite this
The mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice. / Martin, Lee J; Semenkow, Samantha; Hanaford, Allison; Wong, Margaret.
In: Neurobiology of Aging, Vol. 35, No. 5, 05.2014, p. 1132-1152.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice
AU - Martin, Lee J
AU - Semenkow, Samantha
AU - Hanaford, Allison
AU - Wong, Margaret
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
KW - Adenine nucleotide translocase
KW - Cerebellum
KW - Interneuron
KW - Porin
KW - Ppif
KW - Voltage-dependent anion channel 1
UR - http://www.scopus.com/inward/record.url?scp=84893769413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893769413&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2013.11.008
DO - 10.1016/j.neurobiolaging.2013.11.008
M3 - Article
C2 - 24325796
AN - SCOPUS:84893769413
VL - 35
SP - 1132
EP - 1152
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 5
ER -