H.-Q.W. and Y.I. equally contributed to this work.
Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss
Article first published online: 7 AUG 2008
© 2008 The Authors. Journal Compilation © 2008 International Society for Neurochemistry
Journal of Neurochemistry
Volume 107, Issue 1, pages 171–185, October 2008
How to Cite
Wang, H.-Q., Imai, Y., Inoue, H., Kataoka, A., Iita, S., Nukina, N. and Takahashi, R. (2008), Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss. Journal of Neurochemistry, 107: 171–185. doi: 10.1111/j.1471-4159.2008.05607.x
- Issue published online: 16 SEP 2008
- Article first published online: 7 AUG 2008
- Received March 6, 2008; revised manuscript received July 17, 2008; accepted July 18, 2008.
- dopaminergic neuron;
- endoplasmic reticulam stress;
- mitochondrial complex I;
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.