Journal Article

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

Yasuko Kitao, Yuzuru Imai, Kentaro Ozawa, Ayane Kataoka, Toshio Ikeda, Mariko Soda, Kazuhiko Nakimawa, Hiroshi Kiyama, David M. Stern, Osamu Hori, Kazumasa Wakamatsu, Shosuke Ito, Shigeyoshi Itohara, Ryosuke Takahashi and Satoshi Ogawa

in Human Molecular Genetics

Volume 16, issue 1, pages 50-60
Published in print January 2007 | ISSN: 0964-6906
Published online November 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl439
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

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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.

Journal Article.  7004 words.  Illustrated.

Subjects: Genetics and Genomics

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