Parkin and Endoplasmic Reticulum Stress

Abstract: 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 NH2 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.

[1]  M. Yokochi.  Development of the nosological analysis of juvenile parkinsonism , 2000, Brain and Development.

[2]  Junying Yuan,et al.  Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β , 2000, Nature.

[3]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[4]  K. Su,et al.  A novel endothelin receptor type-B-like gene enriched in the brain. , 1997, Biochemical and biophysical research communications.

[5]  A. Weissman,et al.  RING Finger Proteins Mediators of Ubiquitin Ligase Activity , 2000, Cell.

[6]  T. Dawson,et al.  Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Y. Imai,et al.  Parkin Suppresses Unfolded Protein Stress-induced Cell Death through Its E3 Ubiquitin-protein Ligase Activity* , 2000, The Journal of Biological Chemistry.

[8]  A. Ciechanover,et al.  The ubiquitin system. , 1998, Annual review of biochemistry.

[9]  Y. Yamamura,et al.  Paralysis agitans of early onset with marked diurnal fluctuation of symptoms , 1973, Neurology.

[10]  Shinsei Minoshima,et al.  Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase , 2000, Nature Genetics.

[11]  A. Goldberg,et al.  Cellular Defenses against Unfolded Proteins A Cell Biologist Thinks about Neurodegenerative Diseases , 2001, Neuron.

[12]  F. Urano,et al.  Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. , 2000, Science.

[13]  Satoshi Omura,et al.  Degradation of CFTR by the ubiquitin-proteasome pathway , 1995, Cell.

[14]  N. Hattori,et al.  An Unfolded Putative Transmembrane Polypeptide, which Can Lead to Endoplasmic Reticulum Stress, Is a Substrate of Parkin , 2001, Cell.

[15]  R. Jensen,et al.  A human gene encodes a putative G protein-coupled receptor highly expressed in the central nervous system. , 1998, Brain research. Molecular brain research.

[16]  A. Ishikawa,et al.  Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism , 1996, Neurology.

[17]  R. Plemper,et al.  Retrograde protein translocation: ERADication of secretory proteins in health and disease. , 1999, Trends in biochemical sciences.