Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by mutations in the parkin gene. Parkin protein is characterized by a ubiquitin-like domain at its NH(2) terminus and by two RING finger motifs and one IBR (in between RING finger) motif at its COOH-terminus (RING-IBR-RING). We showed that the parkin protein is an E3 ubiquitin ligase, which binds to ubiquitin-conjugating enzymes (E2s) through its RING-IBR-RING motif. The pathogenesis of AR-JP, therefore, was hypothesized to be accumulation of unidentified neurotoxic protein (a substrate of parkin). On the basis of this hypothesis, the substrate of parkin was sought using a yeast two-hybrid system. A putative G protein-coupled transmembrane polypeptide, named Pael (parkin-associated endothelin receptor-like) receptor, was identified as a parkin binding protein. When overexpressed in cells, this receptor tends to become unfolded, insoluble, and ubiquitinated. The insoluble Pael receptor leads to endoplasmic reticulum (ER) stress-induced cell death. Parkin specifically ubiquitinates this receptor in the presence of ER-resident E2s and promotes the degradation of unfolded Pael receptor, resulting in suppression of the cell death induced by the accumulation of unfolded Pael receptor in the ER. Moreover, the insoluble form of Pael receptor accumulates in the brain of AR-JP patients. This protein is highly expressed in the dopaminergic neurons in the substantia nigra, which is specifically affected in Parkinson's disease; although it is also widely expressed in oligodendroglias in the fiber tract. In conclusion, we showed that the accumulation of unfolded Pael receptor (a substrate of parkin) may cause selective death of dopaminergic neurons in AR-JP.