Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss.
Parkin, a ubiquitin ligase, is responsible for autosomal recessive juvenile parkinsonism (AR-JP). We identified parkin-associated endothelin receptor-like receptor (Pael-R) as a substrate of parkin, whose accumulation is thought to induce unfolded protein response (UPR) -mediated cell death, leading to dopaminergic neurodegeneration. To create an animal model of AR-JP, we generated parkin knockout/Pael-R transgenic (parkin-ko/Pael-R-tg) mice. parkin-ko/Pael-R-tg mice exhibited early and progressive loss of dopaminergic as well as noradrenergic neurons without formation of inclusion bodies, recapitulating the pathological features of AR-JP. Evidence of activation of UPR and up-regulation of dopamine and its metabolites were observed throughout the lifetime. Moreover, complex I activity of mitochondria isolated from parkin-ko/Pael-R-tg mice was significantly reduced later in life. These findings suggest that persistent induction of unfolded protein stress underlies chronic progressive catecholaminergic neuronal death, and that dysfunction of mitochondrial complex I and oxidative stress might be involved in the progression of Parkinson's disease. parkin-ko/Pael-R-tg mice represents an AR-JP mouse model displaying chronic and selective loss of catecholaminergic neurons.
Wang
Hua-Qin
HQ
Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Imai
Yuzuru
Y
Inoue
Haruhisa
H
Kataoka
Ayane
A
Iita
Sachiko
S
Nukina
Nobuyuki
N
Takahashi
Ryosuke
R
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002395:Catecholamines / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017510:Protein Folding; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D002395:Catecholamines; C480827:GPR37 receptor, human; D043562:Receptors, G-Protein-Coupled; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D042967:Electron Transport Complex I; D004298:Dopamine; D009638:Norepinephrine