28 June, 2001. Researchers at Japan's Juntendo University School of Medicine report in tomorrow's Cell that they have identified a novel substrate for the parkin E3 ligase function (see previous story below.) Yuzuru Imai, Ryosuke Takahashi and colleagues describe cell culture experiments suggesting that a transmembrane polypeptide is being ubiquitinated by parkin in an attempt by the cell to degrade an unfolded protein that would otherwise cause neuronal death. The authors claim that parkin mutations in the autosomal recessive, early-onset form of Parkinson's, AR-JP, allow this protein to accumulate, thus causing disease.
The study places this form of Parkinson's in the context of ER stress and the unfolded protein response. Previous research in this area has established that an excess of unfolded proteins in the ER can lead to cell death, and that the cell normally prevents damage by expressing a series of genes. Some of these eject aberrant proteins from the ER back to the cytosol, where they are ubiquitinated and degraded with the help of ER-associated ubiquitin-conjugating enzymes, or E2s (Abstract);(Abstract).
The present study follows a recent paper (Abstract) in which Imai et al. showed that unfolded protein stress induces the upregulation of parkin, and that overexpression of parkin can suppress cell death induced by ER stress.
In this study, Imai et al. ran yeast two-hybrid screens of human brain cDNA libraries using parkin as bait. They identified a clone homologous to endothelin receptor type B and called it Pael-R (parkin-associated endothelin receptor-like receptor). Then they showed that-in cell culture-unfolded protein stress tends to make Pael-R unfold, come out of solution and induce cell death, and that Pael-R appears to be a substrate for parkin, which suppresses its accumulation and subsequent cell death. Finally, they show that Pael-R was accumulated in the brains of four patients with AR-JP relative to two control brains.—Gabrielle Strobel
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- Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell. 2001 Jun 29;105(7):891-902. PubMed.