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Gene Review

Park2  -  parkin RBR E3 ubiquitin protein ligase

Rattus norvegicus

Synonyms: E3 ubiquitin-protein ligase parkin, Park, Prkn
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Disease relevance of Park2

  • Mutations in the parkin gene are linked to autosomal-recessive juvenile parkinsonism (AR-JP) [1].
  • Mutations in the alpha-synuclein and parkin genes cause heritable forms of Parkinson's disease [2].
  • To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P alpha-synuclein in a rat lentiviral model of PD [3].
  • SNX-111 (NEUREX Corporation, Menlo Park, CA, U.S.A.) an omega-conopeptide, was tested for cytoprotection following normothermic ischemia using both a four-vessel occlusion model of severe forebrain ischemia and a model of transient middle cerebral artery occlusion focal ischemia [4].
  • Genetic influences on energy, balance and body weight were studied in four strains of rat (male Sprague-Dawley, Lister Hooded and Alderley Park, and male and female hybrid wild/Sprague-Dawley), maintained for 15 days on either a stock or cafeteria diet [5].

High impact information on Park2

  • Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease [3].
  • Together, these results suggest that Parkin may promote the degradation of substrates localized in mitochondria and involved in the late mitochondrial phase of ceramide-mediated cell death [6].
  • Parkin gene mutations have been implicated in autosomal-recessive early-onset parkinsonism and lead to specific degeneration of dopaminergic neurons in midbrain [6].
  • Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD [7].
  • Furthermore, the cytoprotective effect of parkin on alpha-synuclein-induced cell death was not inhibited in the presence of a proteasome inhibitor [2].

Chemical compound and disease context of Park2

  • We previously reported that haloperidol, a dopamine-D(2) receptor antagonist, induced striatal expression of parkin gene, which mutations cause autosomal recessive juvenile parkinsonism [8].
  • Pregnant Sprague-Dawley (SD) and Alderley Park (Wistar derived) rats were exposed by gavage during gestation days 6-21 to 20 microg/kg, 100 microg/kg, or 50 mg/kg body weight of BPA with ethinylestradiol (EE; 200 microg/kg) acting as a positive control agent [9].
  • Research results at Roswell Park memorial Institute have associated lower levels of intake of dietary vitamin A with a slightly elevated risk of breast cancer [10].

Biological context of Park2

  • The cell specific differences argue in favour of different cellular binding sites and substrates for the protein and a pathogenic role for astrocytes in Parkinson's disease caused by parkin dysfunction [11].
  • The encoded parkin isoforms have different amino acid composition, post-translational modifications, and, most important, molecular architectures [12].
  • These results suggest that temporary suppression of gene expression of parkin and Pael-R may be associated with the METH-induced dopaminergic neurotoxicity [8].
  • Coagulation and fibrinolysis parameters obtained from portal blood were correlated to fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance) and intestinal injury (histological evaluation by Park/Chiu score) [13].
  • Recent studies have shown that the expression of mDab2 is markedly up-regulated during the retinoic acid (RA)-induced differentiation of F9 cells, suggesting another role for mDab2 in cell differentiation [Cho, Lee and Park (1999) Mol. Cells 9, 179-184) [14].

Anatomical context of Park2


Associations of Park2 with chemical compounds


Other interactions of Park2


Analytical, diagnostic and therapeutic context of Park2


  1. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Dong, Z., Ferger, B., Paterna, J.C., Vogel, D., Furler, S., Osinde, M., Feldon, J., Büeler, H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Parkin cleaves intracellular alpha-synuclein inclusions via the activation of calpain. Kim, S.J., Sung, J.Y., Um, J.W., Hattori, N., Mizuno, Y., Tanaka, K., Paik, S.R., Kim, J., Chung, K.C. J. Biol. Chem. (2003) [Pubmed]
  3. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. Lo Bianco, C., Schneider, B.L., Bauer, M., Sajadi, A., Brice, A., Iwatsubo, T., Aebischer, P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. A selective N-type Ca(2+)-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia. Buchan, A.M., Gertler, S.Z., Li, H., Xue, D., Huang, Z.G., Chaundy, K.E., Barnes, K., Lesiuk, H.J. J. Cereb. Blood Flow Metab. (1994) [Pubmed]
  5. Effects of feeding a "cafeteria" diet on energy balance and diet-induced thermogenesis in four strains of rat. Rothwell, N.J., Saville, M.E., Stock, M.J. J. Nutr. (1982) [Pubmed]
  6. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Darios, F., Corti, O., Lücking, C.B., Hampe, C., Muriel, M.P., Abbas, N., Gu, W.J., Hirsch, E.C., Rooney, T., Ruberg, M., Brice, A. Hum. Mol. Genet. (2003) [Pubmed]
  7. Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Tanaka, Y., Engelender, S., Igarashi, S., Rao, R.K., Wanner, T., Tanzi, R.E., Sawa, A., L Dawson, V., Dawson, T.M., Ross, C.A. Hum. Mol. Genet. (2001) [Pubmed]
  8. Effect of the neurotoxic dose of methamphetamine on gene expression of parkin and Pael-receptors in rat striatum. Nakahara, T., Kuroki, T., Ohta, E., Kajihata, T., Yamada, H., Yamanaka, M., Hashimoto, K., Tsutsumi, T., Hirano, M., Uchimura, H. Parkinsonism Relat. Disord. (2003) [Pubmed]
  9. Normal sexual development of two strains of rat exposed in utero to low doses of bisphenol A. Tinwell, H., Haseman, J., Lefevre, P.A., Wallis, N., Ashby, J. Toxicol. Sci. (2002) [Pubmed]
  10. Diet and the epidemiology of human breast cancer. Mettlin, C. Cancer (1984) [Pubmed]
  11. Astrocytic but not neuronal increased expression and redistribution of parkin during unfolded protein stress. Ledesma, M.D., Galvan, C., Hellias, B., Dotti, C., Jensen, P.H. J. Neurochem. (2002) [Pubmed]
  12. Parkin transcript variants in rat and human brain. Dagata, V., Cavallaro, S. Neurochem. Res. (2004) [Pubmed]
  13. Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion. Schoots, I.G., Levi, M., van Vliet, A.K., Declerck, P.J., Maas, A.M., van Gulik, T.M. Thromb. Haemost. (2004) [Pubmed]
  14. p67 isoform of mouse disabled 2 protein acts as a transcriptional activator during the differentiation of F9 cells. Cho, S.Y., Jeon, J.W., Lee, S.H., Park, S.S. Biochem. J. (2000) [Pubmed]
  15. Acute and chronic haloperidol treatments increase parkin mRNA levels in the rat brain. Nakahara, T., Gotoh, L., Motomura, K., Kawanami, N., Ohta, E., Hirano, M., Uchimura, H. Neurosci. Lett. (2001) [Pubmed]
  16. Distribution of parkin in the adult rat brain. D'Agata, V., Zhao, W., Pascale, A., Zohar, O., Scapagnini, G., Cavallaro, S. Prog. Neuropsychopharmacol. Biol. Psychiatry (2002) [Pubmed]
  17. Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. Ren, Y., Zhao, J., Feng, J. J. Neurosci. (2003) [Pubmed]
  18. Permeation of long-chain fatty acid into adipocytes. Kinetics, specificity, and evidence for involvement of a membrane protein. Abumrad, N.A., Park, J.H., Park, C.R. J. Biol. Chem. (1984) [Pubmed]
  19. Protein kinase activities in rat pancreatic islets of Langerhans. Sugden, M.C., Ashcroft, S.J., Sugden, P.H. Biochem. J. (1979) [Pubmed]
  20. Post-translational modification of the protein-synthesis initiation factor eIF-4D by spermidine in rat hepatoma cells. Gerner, E.W., Mamont, P.S., Bernhardt, A., Siat, M. Biochem. J. (1986) [Pubmed]
  21. Polychlorinated biphenyls alter expression of alpha-synuclein, synaptophysin and parkin in the rat brain. Malkiewicz, K., Mohammed, R., Folkesson, R., Winblad, B., Szutowski, M., Benedikz, E. Toxicol. Lett. (2006) [Pubmed]
  22. Regional and cellular expression of the parkin gene in the rat cerebral cortex. D'Agata, V., Grimaldi, M., Pascale, A., Cavallaro, S. Eur. J. Neurosci. (2000) [Pubmed]
  23. Cloning and distribution of the rat parkin mRNA. D'Agata, V., Zhao, W., Cavallaro, S. Brain Res. Mol. Brain Res. (2000) [Pubmed]
  24. Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson's disease. Yamada, M., Mizuno, Y., Mochizuki, H. Hum. Gene Ther. (2005) [Pubmed]
  25. Regulation of hippocampal parkin protein by corticosteroids. Horowitz, J.M., Pastor, D.M., Kar, S., Arinsburg, S.A., Hallas, B.H., Torres, G. Neuroreport (2003) [Pubmed]
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