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

• The constitutive parkin expression was high in neurons as compared with astrocytes [11].
• Acute haloperidol treatment (2 mg/kg) increased parkin mRNA levels in the striatum and nucleus accumbens but not in the medial prefrontal cortex and substantia nigra [15].
• The authors have recently isolated the mRNA coding for the rat homolog of parkin and showed its widespread expression in the central nervous system (CNS) by in situ hybridization [16].
• Here we report that parkin, a protein-ubiquitin E3 ligase linked to PD, was tightly bound to microtubules in taxol-mediated microtubule coassembly assays [17].
• This study extends our earlier work (Abumrad, N. A., Perkins, R.C., Park, J.H., and Park, C.R. J. Biol. Chem. 256, 9183-9191) which showed that oleate permeates the plasma membrane of the rat adipocyte principally by a transport process with the characteristics of facilitated diffusion [18].

Associations of Park2 with chemical compounds

• We examined the effects of acute and chronic treatment with haloperidol on parkin mRNA expression in the rat brain by reverse transcription-polymerase chain reaction [15].
• Four-week-treatment with haloperidol decanoate (25 mg eq/kg) produced a significant increase in parkin mRNA levels in the striatum without affecting to those in the medial prefrontal cortex, nucleus accumbens and substantia nigra [15].
• Effect of the neurotoxic dose of methamphetamine on gene expression of parkin and Pael-receptors in rat striatum [8].
• One species was the free catalytic subunit of cyclic AMP-dependent protein kinase, two species corresponded to 'Type I' and 'Type II' cyclic AMP-dependent protein kinase holoenzymes [see Corbin, Keely & Park (1975) J. Biol. Chem. 250, 218--225], and the fourth species was a cyclic AMP-independent protein kinase [19].
• Hypusine is selectively formed in the eukaryotic translation initiation factor eIF-4D, by a post-translational mechanism involving spermidine [Cooper, Park, Folk, Safer & Braverman (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 1854-1857] [20].

Other interactions of Park2

• The decrease in alpha-synuclein was accompanied by a transient increase in parkin and synaptophysin levels [21].
• These results suggest that Parkin may be involved in the haloperidol-induced synaptic plasticity, since Parkin regulates the turnover of the synaptic protein, CDCrel-1 [15].
• Taken together, our results show that parkin is a novel tubulin-binding protein, as well as a microtubule-associated protein [17].
• Examination of mixed cortical neuro-glial cultures by indirect immunofluorescence technique coupled to traditional epifluorescence and confocal microscopy analysis demonstrated the expression of parkin in the cytoplasm and neurites of neurons, and its absence in glial fibrillary acidic protein (GFAP)-positive astrocytes [22].

Analytical, diagnostic and therapeutic context of Park2

• RT-PCR and in situ hybridization revealed widespread expression of parkin in the rat brain and the periphery [23].
• We have isolated by RT-PCR and sequenced a partial cDNA coding for the rat homolog of parkin, a gene mutated in autosomal recessive juvenile parkinsonism [23].
• Immunohistochemistry on adult rat brain sections showed a widespread distribution of parkin [16].
• Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson's disease [24].
• To understand the relationship between parkin and circulating corticosteroid hormones, we studied the long-term depletion of corticosterone due to bilateral adrenalectomy in rats [25].

References