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.
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.
Kitao
Yasuko
Y
Department of Neuroanatomy, Kanazawa University Medical School, 13-1, Takara-machi, Kanazawa City, 920-8640 Ishikawa, Japan. kitao@nanat.m.kanazawa-u.ac.jp
Imai
Yuzuru
Y
Ozawa
Kentaro
K
Kataoka
Ayane
A
Ikeda
Toshio
T
Soda
Mariko
M
Nakimawa
Kazuhiko
K
Kiyama
Hiroshi
H
Stern
David M
DM
Hori
Osamu
O
Wakamatsu
Kazumasa
K
Ito
Shosuke
S
Itohara
Shigeyoshi
S
Takahashi
Ryosuke
R
Ogawa
Satoshi
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016923:Cell Death; D004298:Dopamine / Q000096:biosynthesis / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding; D011506:Proteins / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C480827:GPR37 receptor, human; D018840:HSP70 Heat-Shock Proteins; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; C050087:oxygen-regulated proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine