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Gene Review

PARK2  -  parkin RBR E3 ubiquitin protein ligase

Homo sapiens

Synonyms: AR-JP, E3 ubiquitin-protein ligase parkin, LPRS2, PDJ, PRKN, ...
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Disease relevance of PARK2


Psychiatry related information on PARK2


High impact information on PARK2

  • Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage [12].
  • In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology [12].
  • Here, we have identified Parc, a Parkin-like ubiquitin ligase, as a cytoplasmic anchor protein in p53-associated protein complexes [13].
  • Parkin specifically ubiquitinates this receptor in the presence of ubiquitin-conjugating enzymes resident in the endoplasmic reticulum and promotes the degradation of insoluble Pael receptor, resulting in suppression of the cell death induced by Pael receptor overexpression [14].
  • An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin [14].

Chemical compound and disease context of PARK2


Biological context of PARK2

  • With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy [20].
  • Loss of heterozygosity analysis of primary ovarian tumors by use of polymorphic markers in the 6q26 region demonstrated 72% LOH in the center of the PARK2 gene, the highest of any of the markers tested [21].
  • A gene for autosomal recessive juvenile parkinsonism (ARJP; HGMW-approved symbol PARK2; MIM 600116) has recently been mapped to a 17-cM interval on chromosome 6q25.2-q27 [22].
  • Although within the PARK2/PACRG gene cluster the PARK2_e01(-2599) allele T was most strongly associated with leprosy (OR approximately 3-5), the association with typhoid is much less strong [3].
  • Autosomal recessive mutations in the parkin gene (PARK2) have been identified as a common cause of familial and also sporadic, early-onset parkinsonism (EOPD): point mutations, exonic deletions, and duplications or triplications have been described [23].

Anatomical context of PARK2

  • We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples [2].
  • The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies [24].
  • Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells [25].
  • These findings demonstrate that Parkin is an E3 enzyme and suggest that it is involved in the ubiquitination pathway for misfolded proteins derived from endoplasmic reticulum and contributes to protection from neurotoxicity induced by unfolded protein stresses [26].
  • Double labeling with confocal microscopy of DLB midbrain sections revealed that approximately 90% of anti-alpha S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353 [7].

Associations of PARK2 with chemical compounds

  • These patients were evaluated previously for the presence of parkin mutations (PARK2) and were found to be negative [27].
  • Because both Parkin and alpha-synuclein can regulate the activity of the dopamine transporter, we investigated whether they influenced ubiquitin lysine 63-linked chain assembly [28].
  • We determined that Parkin functions with UbcH13/Uev1a, a dimeric ubiquitin-conjugating enzyme, to assemble ubiquitin lysine 63-linked chains [28].
  • Heterozygous carriers of a single Park2 mutation either were asymptomatic or developed clinical symptoms in late adulthood or after brief exposure to haloperidol therapy [29].
  • Additionally, we show sensitivity of both endogenous synphilin-1 and parkin to proteolytic dysfunction and their co-localization in aggresomes formed in response to the proteasome inhibitor MG-132 [30].
  • 2-Mercaptoethanol (2-ME) and tunicamycin increased the expression of parkin in SH-SY5Y (H) cells, Neuro2a cells, Goto-P3 cells, but not in SH-SY5Y (J) cells and IMR32 cells [31].
  • Compound heterozygous parkin mutations (EX 3_6 del and EX 5 del) caused EOPD in this family, but the A265G variant in the HS1BP3 gene, previously considered to be responsible for ET, was probably not pathogenically related to the ET in this family [32].

Physical interactions of PARK2


Enzymatic interactions of PARK2


Regulatory relationships of PARK2


Other interactions of PARK2

  • These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1 [24].
  • We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions [24].
  • A small proportion of the cells overexpressing LRRK2 contain protein aggregates, and this proportion is greatly increased by coexpression of parkin [41].
  • RT-PCR analysis of the eight genes localizing to FRA6E indicated that 50% of the genes, including PARK2, were down-regulated in one or more of the primary ovarian tumors analyzed [21].
  • Moreover, insoluble Pael-R accumulates in the brains of AR-JP patients [36].

Analytical, diagnostic and therapeutic context of PARK2


  1. Dopamine covalently modifies and functionally inactivates parkin. LaVoie, M.J., Ostaszewski, B.L., Weihofen, A., Schlossmacher, M.G., Selkoe, D.J. Nat. Med. (2005) [Pubmed]
  2. Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia. Agirre, X., Román-Gómez, J., Vázquez, I., Jiménez-Velasco, A., Garate, L., Montiel-Duarte, C., Artieda, P., Cordeu, L., Lahortiga, I., Calasanz, M.J., Heiniger, A., Torres, A., Minna, J.D., Prósper, F. Int. J. Cancer (2006) [Pubmed]
  3. PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever. Ali, S., Vollaard, A.M., Widjaja, S., Surjadi, C., van de Vosse, E., van Dissel, J.T. Clin. Exp. Immunol. (2006) [Pubmed]
  4. Susceptibility to leprosy is associated with PARK2 and PACRG. Mira, M.T., Alcaïs, A., Nguyen, V.T., Moraes, M.O., Di Flumeri, C., Vu, H.T., Mai, C.P., Nguyen, T.H., Nguyen, N.B., Pham, X.K., Sarno, E.N., Alter, A., Montpetit, A., Moraes, M.E., Moraes, J.R., Doré, C., Gallant, C.J., Lepage, P., Verner, A., Van De Vosse, E., Hudson, T.J., Abel, L., Schurr, E. Nature (2004) [Pubmed]
  5. Phosphorylation of Parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. Avraham, E., Rott, R., Liani, E., Szargel, R., Engelender, S. J. Biol. Chem. (2007) [Pubmed]
  6. alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease. Kawahara, K., Hashimoto, M., Bar-On, P., Ho, G.J., Crews, L., Mizuno, H., Rockenstein, E., Imam, S.Z., Masliah, E. J. Biol. Chem. (2008) [Pubmed]
  7. Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Schlossmacher, M.G., Frosch, M.P., Gai, W.P., Medina, M., Sharma, N., Forno, L., Ochiishi, T., Shimura, H., Sharon, R., Hattori, N., Langston, J.W., Mizuno, Y., Hyman, B.T., Selkoe, D.J., Kosik, K.S. Am. J. Pathol. (2002) [Pubmed]
  8. Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations. Kumru, H., Santamaria, J., Tolosa, E., Valldeoriola, F., Muñoz, E., Marti, M.J., Iranzo, A. Ann. Neurol. (2004) [Pubmed]
  9. Cardiac sympathetic denervation in Lewy body disease. Orimo, S., Amino, T., Takahashi, A., Kojo, T., Uchihara, T., Mori, F., Wakabayashi, K., Takahashi, H. Parkinsonism Relat. Disord. (2006) [Pubmed]
  10. Co-occurrence of restless legs syndrome and Parkin mutations in two families. Adel, S., Djarmati, A., Kabakci, K., Pichler, I., Eskelson, C., Lohnau, T., Kock, N., Hagenah, J., Hedrich, K., Schwinger, E., Kramer, P.L., Pramstaller, P.P., Klein, C. Mov. Disord. (2006) [Pubmed]
  11. Parkin mutation associated parkinsonism and cognitive decline, comparison to early onset Parkinson's disease. Benbunan, B.R., Korczyn, A.D., Giladi, N. Journal of neural transmission (Vienna, Austria : 1996) (2004) [Pubmed]
  12. The biochemistry of Parkinson's disease. Cookson, M.R. Annu. Rev. Biochem. (2005) [Pubmed]
  13. Parc: a cytoplasmic anchor for p53. Nikolaev, A.Y., Li, M., Puskas, N., Qin, J., Gu, W. Cell (2003) [Pubmed]
  14. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Imai, Y., Soda, M., Inoue, H., Hattori, N., Mizuno, Y., Takahashi, R. Cell (2001) [Pubmed]
  15. Parkin: a multipurpose neuroprotective agent? Feany, M.B., Pallanck, L.J. Neuron (2003) [Pubmed]
  16. Parkin increases dopamine uptake by enhancing the cell surface expression of dopamine transporter. Jiang, H., Jiang, Q., Feng, J. J. Biol. Chem. (2004) [Pubmed]
  17. Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2. Orimo, S., Amino, T., Yokochi, M., Kojo, T., Uchihara, T., Takahashi, A., Wakabayashi, K., Takahashi, H., Hattori, N., Mizuno, Y. Mov. Disord. (2005) [Pubmed]
  18. Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Jiang, H., Ren, Y., Zhao, J., Feng, J. Hum. Mol. Genet. (2004) [Pubmed]
  19. Diverse effects of pathogenic mutations of Parkin that catalyze multiple monoubiquitylation in vitro. Matsuda, N., Kitami, T., Suzuki, T., Mizuno, Y., Hattori, N., Tanaka, K. J. Biol. Chem. (2006) [Pubmed]
  20. Genetic dissection of immunity in leprosy. Alcaïs, A., Mira, M., Casanova, J.L., Schurr, E., Abel, L. Curr. Opin. Immunol. (2005) [Pubmed]
  21. Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Denison, S.R., Callahan, G., Becker, N.A., Phillips, L.A., Smith, D.I. Genes Chromosomes Cancer (2003) [Pubmed]
  22. A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2). Matsumine, H., Yamamura, Y., Hattori, N., Kobayashi, T., Kitada, T., Yoritaka, A., Mizuno, Y. Genomics (1998) [Pubmed]
  23. Deletion of the parkin and PACRG gene promoter in early-onset parkinsonism. Lesage, S., Magali, P., Lohmann, E., Lacomblez, L., Teive, H., Janin, S., Cousin, P.Y., D??rr, A., Brice, A. Hum. Mutat. (2007) [Pubmed]
  24. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Chung, K.K., Zhang, Y., Lim, K.L., Tanaka, Y., Huang, H., Gao, J., Ross, C.A., Dawson, V.L., Dawson, T.M. Nat. Med. (2001) [Pubmed]
  25. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Moore, D.J., Zhang, L., Troncoso, J., Lee, M.K., Hattori, N., Mizuno, Y., Dawson, T.M., Dawson, V.L. Hum. Mol. Genet. (2005) [Pubmed]
  26. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. Imai, Y., Soda, M., Takahashi, R. J. Biol. Chem. (2000) [Pubmed]
  27. Lack of mutations in DJ-1 in a cohort of Taiwanese ethnic Chinese with early-onset parkinsonism. Lockhart, P.J., Bounds, R., Hulihan, M., Kachergus, J., Lincoln, S., Lin, C.H., Wu, R.M., Farrer, M.J. Mov. Disord. (2004) [Pubmed]
  28. Alpha-synuclein and parkin contribute to the assembly of ubiquitin lysine 63-linked multiubiquitin chains. Doss-Pepe, E.W., Chen, L., Madura, K. J. Biol. Chem. (2005) [Pubmed]
  29. Molecular findings in familial Parkinson disease in Spain. Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jiménez-Jiménez, F.J., Berciano, J., del Ser, T., Jiménez, A., Ruíz, P.G., de Yébenes, J.G. Arch. Neurol. (2002) [Pubmed]
  30. Synphilin-1 and parkin show overlapping expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Bandopadhyay, R., Kingsbury, A.E., Muqit, M.M., Harvey, K., Reid, A.R., Kilford, L., Engelender, S., Schlossmacher, M.G., Wood, N.W., Latchman, D.S., Harvey, R.J., Lees, A.J. Neurobiol. Dis. (2005) [Pubmed]
  31. Cell type-specific upregulation of Parkin in response to ER stress. Wang, H.Q., Imai, Y., Kataoka, A., Takahashi, R. Antioxid. Redox Signal. (2007) [Pubmed]
  32. A family with Parkinson disease, essential tremor, bell palsy, and parkin mutations. Deng, H., Le, W.D., Hunter, C.B., Mejia, N., Xie, W.J., Jankovic, J. Arch. Neurol. (2007) [Pubmed]
  33. Co-association of parkin and alpha-synuclein. Choi, P., Golts, N., Snyder, H., Chong, M., Petrucelli, L., Hardy, J., Sparkman, D., Cochran, E., Lee, J.M., Wolozin, B. Neuroreport (2001) [Pubmed]
  34. The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI. Huynh, D.P., Scoles, D.R., Nguyen, D., Pulst, S.M. Hum. Mol. Genet. (2003) [Pubmed]
  35. Parkin ubiquitinates and promotes the degradation of RanBP2. Um, J.W., Min, d.o. .S., Rhim, H., Kim, J., Paik, S.R., Chung, K.C. J. Biol. Chem. (2006) [Pubmed]
  36. Pael receptor, endoplasmic reticulum stress, and Parkinson's disease. Takahashi, R., Imai, Y. J. Neurol. (2003) [Pubmed]
  37. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Shimura, H., Schlossmacher, M.G., Hattori, N., Frosch, M.P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K.S., Selkoe, D.J. Science (2001) [Pubmed]
  38. A product of the human gene adjacent to parkin is a component of Lewy bodies and suppresses Pael receptor-induced cell death. Imai, Y., Soda, M., Murakami, T., Shoji, M., Abe, K., Takahashi, R. J. Biol. Chem. (2003) [Pubmed]
  39. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Zhang, Y., Gao, J., Chung, K.K., Huang, H., Dawson, V.L., Dawson, T.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  40. Clinical features and gene analysis in Korean patients with early-onset Parkinson disease. Chung, E.J., Ki, C.S., Lee, W.Y., Kim, I.S., Kim, J.Y. Arch. Neurol. (2006) [Pubmed]
  41. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Smith, W.W., Pei, Z., Jiang, H., Moore, D.J., Liang, Y., West, A.B., Dawson, V.L., Dawson, T.M., Ross, C.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  42. Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer. Letessier, A., Garrido-Urbani, S., Ginestier, C., Fournier, G., Esterni, B., Monville, F., Ad??la??de, J., Geneix, J., Xerri, L., Dubreuil, P., Viens, P., Charafe-Jauffret, E., Jacquemier, J., Birnbaum, D., Lopez, M., Chaffanet, M. Oncogene (2007) [Pubmed]
  43. Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson's disease. Yamada, M., Mizuno, Y., Mochizuki, H. Hum. Gene Ther. (2005) [Pubmed]
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