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
N1 - Funding Information:
The authors thank Ann Price and Yan Pan for their outstanding technical work and Isabella Martin for her editorial assistance. This work was supported by grant NS034100 and NS052098 from the NIH-NINDS and AG016282 from the NIH-NIA .
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
SN - 0197-4580
VL - 35
SP - 1132
EP - 1152
JO - Neurobiology of aging
JF - Neurobiology of aging
IS - 5
ER -