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Gene Review

Park2  -  Parkinson disease (autosomal recessive,...

Mus musculus

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


Psychiatry related information on Park2


High impact information on Park2

  • Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism [7].
  • Therefore, parkin and alpha-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons [8].
  • Intriguingly, alpha-synuclein (alpha-SN), another familial Parkinson's disease (PD) gene product, abrogated the 14-3-3eta-induced suppression of parkin activity. alpha-SN could bind tightly to 14-3-3eta and consequently sequester it from the parkin-14-3-3eta complex [9].
  • To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2 [10].
  • Moreover, catecholamine levels in the striatum, olfactory bulb, and spinal cord of Parkin-deficient mice were normal [10].

Chemical compound and disease context of Park2


Biological context of Park2


Anatomical context of Park2

  • The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease [1].
  • Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy [18].
  • Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin [18].
  • Many sporadic PD patients have a defect in mitochondria respiration, and some of the genes that cause PD are mitochondrial-related (e.g., PINK1, Parkin, DJ1) [19].
  • Cannabinoid CB(1) receptors in the basal ganglia and motor response to activation or blockade of these receptors in parkin-null mice [20].

Associations of Park2 with chemical compounds

  • Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice [1].
  • The levels of glutathione were further increased in parkin null mice than in controls both with and without treatment with l-DOPA, suggesting that a compensatory mechanism may protect DA neurones from neuronal death [15].
  • Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline [2].
  • Our results show that Parkin and DJ-1 inhibit dopamine neuron death and enhance amphetamine-induced dopaminergic function in a mouse model of idiopathic PD [3].
  • These changes are associated with differences in behavioral responses to cannabinoid agonists or antagonists between Park-2 knockout and wild-type mice, although parkin-null mice exhibited evident gender-dependent differences for both levels of CB(1) receptors and motor responses to agonists or antagonists [20].

Other interactions of Park2

  • It's a double knock-out! The quaking mouse is a spontaneous deletion of parkin and parkin co-regulated gene (PACRG) [17].
  • We have identified the mouse mutant Quaking as a spontaneously occurring PRKN knockout [17].
  • MPTP drastically reduced dopamine to 19% of normal levels and neither DJ-1 nor Parkin protected against MPTP-induced catecholamine loss under these conditions [3].
  • Septin 5, a parkin substrate, is a vesicle- and membrane-associated protein that plays a significant role in inhibiting exocytosis [4].
  • By contrast, the administration of the CB(1) receptor antagonist SR141716 resulted in a hyperkinetic response in parkin-null mice, response that was almost absent in wild-type animals and that was accompanied by a decrease in tyrosine hydroxylase activity in the caudate-putamen [20].

Analytical, diagnostic and therapeutic context of Park2

  • The PK-KO mice, however, are not only resistant to the l-DOPA-induced pro-apoptotic effects but they have an increased number of TH-immunoreactive neurones after treatment with l-DOPA, suggesting that l-DOPA is toxic for neurones of WT mice but not those of parkin null mice [15].
  • Animal models provide a useful tool for the study of development and disease, and the recent production of transgenic fly and mouse parkin deficient models allows investigation of the molecular role of parkin in dopamine regulation and nigrostriatal function [17].
  • These results warrant further exploration of DJ-1 and Parkin gene therapy for PD, although a better understanding of their effects on behavior and dopamine neurotransmission is required before these proteins can be safely used.Molecular Therapy (2007) 15 4, 698-704. doi:10.1038/ [3].
  • Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period [5].
  • The antibodies were shown to be specific using Western blot analysis, immunostaining of cells transfected with mouse Parkin and pre-absorption tests [21].


  1. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. Goldberg, M.S., Fleming, S.M., Palacino, J.J., Cepeda, C., Lam, H.A., Bhatnagar, A., Meloni, E.G., Wu, N., Ackerson, L.C., Klapstein, G.J., Gajendiran, M., Roth, B.L., Chesselet, M.F., Maidment, N.T., Levine, M.S., Shen, J. J. Biol. Chem. (2003) [Pubmed]
  2. Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. Casarejos, M.J., Menéndez, J., Solano, R.M., Rodríguez-Navarro, J.A., García de Yébenes, J., Mena, M.A. J. Neurochem. (2006) [Pubmed]
  3. DJ-1 and Parkin Modulate Dopamine-dependent Behavior and Inhibit MPTP-induced Nigral Dopamine Neuron Loss in Mice. Paterna, J.C., Leng, A., Weber, E., Feldon, J., Büeler, H. Mol. Ther. (2007) [Pubmed]
  4. Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons. Son, J.H., Kawamata, H., Yoo, M.S., Kim, D.J., Lee, Y.K., Kim, S., Dawson, T.M., Zhang, H., Sulzer, D., Yang, L., Beal, M.F., Degiorgio, L.A., Chun, H.S., Baker, H., Peng, C. J. Neurochem. (2005) [Pubmed]
  5. Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease? Mengesdorf, T., Jensen, P.H., Mies, G., Aufenberg, C., Paschen, W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  6. Effects of cinnarizine, a calcium antagonist that produces human parkinsonism, in parkin knock out mice. Serrano, A., Menéndez, J., Casarejos, M.J., Solano, R.M., Gallego, E., Sánchez, M., Mena, M.A., García de Yebenes, J. Neuropharmacology (2005) [Pubmed]
  7. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., Shimizu, N. Nature (1998) [Pubmed]
  8. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Petrucelli, L., O'Farrell, C., Lockhart, P.J., Baptista, M., Kehoe, K., Vink, L., Choi, P., Wolozin, B., Farrer, M., Hardy, J., Cookson, M.R. Neuron (2002) [Pubmed]
  9. 14-3-3eta is a novel regulator of parkin ubiquitin ligase. Sato, S., Chiba, T., Sakata, E., Kato, K., Mizuno, Y., Hattori, N., Tanaka, K. EMBO J. (2006) [Pubmed]
  10. Parkin-deficient mice are not a robust model of parkinsonism. Perez, F.A., Palmiter, R.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. Midbrain neuronal cultures from parkin mutant mice are resistant to nitric oxide-induced toxicity. Solano, R.M., Menéndez, J., Casarejos, M.J., Rodríguez-Navarro, J.A., García de Yébenes, J., Mena, M.A. Neuropharmacology (2006) [Pubmed]
  12. Parkin suppresses the expression of monoamine oxidases. Jiang, H., Jiang, Q., Liu, W., Feng, J. J. Biol. Chem. (2006) [Pubmed]
  13. Parkin attenuates manganese-induced dopaminergic cell death. Higashi, Y., Asanuma, M., Miyazaki, I., Hattori, N., Mizuno, Y., Ogawa, N. J. Neurochem. (2004) [Pubmed]
  14. Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity. Perez, F.A., Curtis, W.R., Palmiter, R.D. BMC neuroscience [electronic resource]. (2005) [Pubmed]
  15. Differential effects of l-DOPA on monoamine metabolism, cell survival and glutathione production in midbrain neuronal-enriched cultures from parkin knockout and wild-type mice. Casarejos, M.J., Solano, R.M., Menéndez, J., Rodríguez-Navarro, J.A., Correa, C., García de Yébenes, J., Mena, M.A. J. Neurochem. (2005) [Pubmed]
  16. Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. Periquet, M., Corti, O., Jacquier, S., Brice, A. J. Neurochem. (2005) [Pubmed]
  17. It's a double knock-out! The quaking mouse is a spontaneous deletion of parkin and parkin co-regulated gene (PACRG). Lockhart, P.J., O'Farrell, C.A., Farrer, M.J. Mov. Disord. (2004) [Pubmed]
  18. Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy. von Coelln, R., Thomas, B., Andrabi, S.A., Lim, K.L., Savitt, J.M., Saffary, R., Stirling, W., Bruno, K., Hess, E.J., Lee, M.K., Dawson, V.L., Dawson, T.M. J. Neurosci. (2006) [Pubmed]
  19. Mitochondria mass is low in mouse substantia nigra dopamine neurons: Implications for Parkinson's disease. Liang, C.L., Wang, T.T., Luby-Phelps, K., German, D.C. Exp. Neurol. (2007) [Pubmed]
  20. Cannabinoid CB(1) receptors in the basal ganglia and motor response to activation or blockade of these receptors in parkin-null mice. González, S., Mena, M.A., Lastres-Becker, I., Serrano, A., de Yébenes, J.G., Ramos, J.A., Fernández-Ruiz, J. Brain Res. (2005) [Pubmed]
  21. Parkin expression in the adult mouse brain. Stichel, C.C., Augustin, M., Kühn, K., Zhu, X.R., Engels, P., Ullmer, C., Lübbert, H. Eur. J. Neurosci. (2000) [Pubmed]
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