Pael receptor, endoplasmic reticulum stress, and Parkinson's disease.
Autosomal recessive juvenile parkinsonism (AR-JP) is caused by mutations of the parkin gene. Parkin is an E3 ubiquitin ligase that specifically recognizes its substrate protein, promoting its ubiquitination and subsequent degradation. Accordingly, we hypothesized that AR-JP may be caused by accumulation of an unidentified neurotoxic protein, which is a substrate of parkin. Based on this hypothesis, we cloned parkin-binding protein using a yeast two-hybrid system and identified a putative G protein-coupled receptor protein,which we named the Pael receptor (Pael-R). When overexpressed in cells, this receptor became unfolded, insoluble, and ubiquitinated. Accumulation of the insoluble Pael-R subsequently led to endoplasmic reticulum (ER) stress-induced cell death. Parkin specifically ubiquitinates the unfolded Pael-R and promotes its degradation, resulting in suppression of cell death induced by the accumulation of unfolded Pael-R. Moreover, insoluble Pael-R accumulates in the brains of AR-JP patients. It is highly expressed by the dopaminergic neurons of the substantia nigra, strongly suggesting that accumulation of unfolded Pael-R may lead to selective death of dopaminergic neurons in AR-JP.Recently, we identified Hsp70 and its co-chaperone CHIP as novel parkin-binding partners. We found that CHIP enhanced parkinmediated ubiquitination of Pael-R. In concert with Hsp70, CHIP also enhanced the ability of parkin to inhibit cell death induced by Pael-R, indicating that CHIP and Hsp70 are both co-factors of parkin.
Laboratory of Motor Neurodegeneration, RIKEN Brain Science Institute (BSI), 2-1 Hirosawa, Wako, 351-0198, Saitama, Japan. ryosuke@brain.riken.go.jp
Ryosuke
R
Takahashi
Yuzuru
Y
Imai
D000818:Animals; D016923:Cell Death; D003067:Coenzymes / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D003067:Coenzymes; C480827:GPR37 receptor, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D019204:GTP-Binding Proteins