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

• Published in: Human molecular genetics 2007-01, Vol.16 (1), p.50-60
• Main Authors: Kitao, Yasuko, Imai, Yuzuru, Ozawa, Kentaro, Kataoka, Ayane, Ikeda, Toshio, Soda, Mariko, Nakimawa, Kazuhiko, Kiyama, Hiroshi, Stern, David M., Hori, Osamu, Wakamatsu, Kazumasa, Ito, Shosuke, Itohara, Shigeyoshi, Takahashi, Ryosuke, Ogawa, Satoshi
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Biological and medical sciences; Cell Death; Cell receptors; Cell structures and functions; Dopamine - biosynthesis; Dopamine - toxicity; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - pathology; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; HSP70 Heat-Shock Proteins; Mice; Mice, Inbred C57BL; Miscellaneous; Molecular and cellular biology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Protein Folding; Proteins - physiology; Receptors, G-Protein-Coupled - metabolism; Receptors, G-Protein-Coupled - physiology; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddl439

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.