Human Molecular Genetics Advance Access originally published online on November 20, 2006
Human Molecular Genetics 2007 16(1):50-60; doi:10.1093/hmg/ddl439
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Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation
1 Department of Neuroanatomy, Kanazawa University Medical School, 13-1, Takara-machi, Kanazawa City, 920-8640 Ishikawa, Japan, 2 Laboratory for Motor System Neurodegeneration and 3 Laboratory for Behavioral Genetics and RIKEN Brain Science Institute (BSI), Saitama 351-0198, Japan, 4 Department of Anatomy and Neurobiology, Osaka City University, Graduate School of Medicine, Osaka, Japan, 5 Department of Neurology, Kyoto University Medical School, Kyoto, Japan, 6 Department of Chemistry, Fujita Health University School of Health Sciences, Aichi 470-1192, Japan and 7 Dean's Office, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
* To whom correspondence should be addressed. Tel: +81 762652162; Fax: +81 762344222; Email: kitao{at}nanat.m.kanazawa-u.ac.jp
Received August 2, 2006; Revised October 19, 2006; Accepted November 13, 2006
Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. Expression of Parkin associated endothelin-receptor like receptor (Pael-R) in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre recombinase into the striatum. Upregulation of Pael-R in the substantia nigra pars compacta of mice by retrograde infection induced endoplasmic reticulum (ER) stress leads to death of dopaminergic neurons. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their decreased survival in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150 (150 kDa oxygen-regulated protein). Dopamine-related toxicity was also a key factor, as a dopamine synthesis inhibitor blocked neuronal death in parkin null mice. These data suggest a model in which ER- and dopamine-related stress are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.
These authors equally contributed to this work.
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