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  • Spatial distribution, cellular integration and stage development of Parkin protein in Xenopus brain. 11172884

    Parkin is an ubiquitin-protein ligase molecule abundantly expressed in mammalian brains. Deletional mutations of Parkin protein produce a disease-related parkinsonian phenotype which is inherited with an autosomal recessive mode of transmission. To gain a greater insight into the evolutionary trajectory of the protein among vertebrate species, we describe here the (i) distribution pattern, (ii) sizing of specific fragments and (iii) embryonic development of Parkin in Xenopus laevis utilizing two antibodies to the N- and C-terminal sequence of the human Parkin protein. Parkin immunoreactivity was distributed in a heterogeneous fashion throughout the adult frog brain. The telencephalon, including the olfactory bulb, striatum and nucleus accumbens, harbored high numbers of Parkin-containing cells. High numbers of immunoreactive neurons were also present in discrete regions of the thalamus and hypothalamus. Relatively moderate expression of Parkin protein was noted in the nucleus anterodorsalis tegmenti, nucleus reticularis medius and torus semicircularis. The substantia nigra exhibited a distinctive heterogeneous pattern of Parkin-immunoreactivity, especially within presumptive dopamine neurons. The cerebellum also showed high expression of Parkin-positive material. Characterization of the subcellular distribution of the protein indicated both a cytoplasmic and nuclear integration of Parkin-immunoreactivity. This pattern of subcellular localization was similar to that observed in human brain material, perhaps reflecting distinct structural phosphorylation sites of the Parkin protein. Western blot analysis identified three specific bands with molecular weights varying from 50 to 65 kDa in adult Xenopus brain. However, studies on the temporal expression of Parkin during development showed a complete absence of cellular immunoreactivity which was especially conspicuous during late premetamorphic stages of frog development. These results suggest that the ubiquitination activity of Parkin is limited or non-existent during embryogenesis, but appears to assume a more functional role during adulthood as reflected by the high distribution pattern of the protein within major circuits of the amphibian brain.
    Document Type:
    Reference
    Product Catalog Number:
    AB5112
    Product Catalog Name:
    Anti-Parkin Antibody, a.a. 305-323

  • Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin ... 23643664

    Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined. Mice were treated with ten injections of either MPTP (20mg/kg; s.c.; every 3.5 days) or saline vehicle (10 ml/kg; s.c.; every 3.5 days). Following a 21 day recovery period, chronic saline- and MPTP-treated mice received an additional injection of either saline (10 ml/kg; s.c.) or MPTP (20mg/kg; s.c.) and were sacrificed 24h later. NSDA neurons displayed significant axon terminal degeneration (as reflected by decreases in DA, tyrosine hydroxylase (TH) and DA transporter concentrations in the striatum) as well as loss of TH-immunoreactive (IR) neurons in the substantia nigra (SN) following MPTP, whereas TIDA neurons revealed no overt axon terminal pathology or loss of TH-IR cell bodies. NSDA neuronal pathology was associated with transient decreases in concentrations of parkin and UCHL-1 protein in the SN, which returned to normal levels by 21 days following cessation of chronic neurotoxicant exposure. Resistance of TIDA neurons to MPTP toxicity was correlated with a transient increase in UCHL-1 and a sustained elevation in parkin in the arcuate nucleus. TIDA neurons represent a DA neuron population with a unique and inherent ability to adapt to acute and chronic toxicant administration with a sustained elevation of the neuroprotective protein parkin. The correlation between the ability to increase parkin and UCHL-1 expression and the resistance of DA neurons to neurotoxicant exposure is consistent with a functional link between these features and an underlying differential susceptibility to toxicant-associated neurodegeneration.
    Document Type:
    Reference
    Product Catalog Number:
    AB152
    Product Catalog Name:
    Anti-Tyrosine Hydroxylase Antibody

  • The effects of oxidative stress on parkin and other E3 ligases. 17883392

    Autosomal recessive mutations within the Parkin gene are associated with degeneration of the substantia nigra and locus coeruleus and an inherited form of Parkinson's disease (PD). As loss-of-function mutations in parkin are responsible for a familial variant of PD, conditions that affect wild-type parkin are likely to be associated with increased risk of idiopathic disease. Previous studies uncovered a unique vulnerability of the parkin protein to dopamine (DA)-induced aggregation and inactivation. In this study, we compared several proteins that share structural elements or ubiquitinating activity with parkin. We report that oxidative stress in several cell lines and primary neurons induces the aggregation of parkin into high molecular weight species, at least a portion of which are self-associated homo-multimers. While parkin was preferentially affected by excess DA, each of the E3 proteins tested were made more insoluble by oxidative stress, and they varied in degree of susceptibility (e.g. parkin > HHARI congruent with CHIP > c-Cbl > E6AP). These conditions of oxidative stress were also associated with decreased parkin E3 ligase activity. Similar to recently conducted studies on alpha-synuclein processing, both macroautophagy and the proteasome participate in parkin degradation, with the proteasome playing the predominant role for normal parkin turnover and macroautophagy being more important in the degradation of aggregated parkin. These data further highlight the selective vulnerability of parkin to DA-induced modifications, demonstrating for the first time the ability of both endogenous and ectopically expressed parkin to transition into an insoluble state in part through self-association and oligomer formation.
    Document Type:
    Reference
    Product Catalog Number:
    AB1761
    Product Catalog Name:
    Anti-Protein Gene Product 9.5 Antibody

  • Characterization of parkin in bovine peripheral nerve. 11879804

    The autosomal recessive juvenile parkinsonism is caused by the mutations of the gene encoding a novel protein called parkin. It has been reported that parkin is expressed in the central nervous system and functions as a ubiquitin-protein ligase (E3) which suppresses neuronal cell degeneration by ubiquitinating misfolded proteins. Thus far, however, it remains unknown if parkin is expressed and functions in the peripheral nervous system. In order to begin to address to this question, we investigated the expression of parkin in bovine peripheral nerve. Reverse transcription polymerase chain reaction analysis demonstrated the presence of parkin transcript in bovine peripheral nerve. The obtained bovine parkin cDNA sequence was identical to that of human except a single nucleotide. Immunoblot analysis demonstrated the expression of parkin protein in bovine peripheral nerve. Immunohistochemical analysis demonstrated the localization of parkin in the axoplasm of myelinated nerve fibers, the Schwann cell cytoplasm and the Schwann cell outer membrane. Furthermore, fractionation analysis indicated the presence of two fractions of parkin in bovine peripheral nerve, the cytosolic fraction and the cell membrane-bound fraction. All together, these results point to diverse roles of parkin in not only the central but also the peripheral nervous system.
    Document Type:
    Reference
    Product Catalog Number:
    AB5112
    Product Catalog Name:
    Anti-Parkin Antibody, a.a. 305-323

  • Alterations in the common fragile site gene Parkin in ovarian and other cancers. 14614460

    The cloning and characterization of the common fragile site (CFS) FRA6E (6q26) identified Parkin, the gene involved in the pathogenesis of many cases of juvenile, early-onset and, rarely, late-onset Parkinson's disease, as the third large gene to be localized within a large CFS. Initial analyses of Parkin indicated that in addition to playing a role in Parkinson's disease, it might also be involved in the development and/or progression of ovarian cancer. These analyses also indicated striking similarities among the large CFS-locus genes: fragile histidine triad gene (FHIT; 3p14.2), WW domain-containing oxidoreductase gene (WWOX; 16q23), and Parkin (6q26). Analyses of FHIT and WWOX in a variety of different cancer types have identified the presence of alternative transcripts with whole exon deletions. Interestingly, various whole exon duplications and deletions have been identified for Parkin in juvenile and early-onset Parkinson's patients. Therefore, we performed mutational/exon rearrangement analysis of Parkin in ovarian cancer cell lines and primary tumors. Four (66.7%) cell lines and four (18.2%) primary tumors were identified as being heterozygous for the duplication or deletion of a Parkin exon. Additionally, three of 23 (13.0%) nonovarian tumor-derived cell lines were also identified as having a duplication or deletion of one or more Parkin exons. Analysis of Parkin protein expression with antibodies revealed that most of the ovarian cancer cell lines and primary tumors had diminished or absent Parkin expression. While functional analyses have not yet been performed for Parkin, these data suggest that like FHIT and WWOX, Parkin may represent a tumor suppressor gene.
    Document Type:
    Reference
    Product Catalog Number:
    AB5112
    Product Catalog Name:
    Anti-Parkin Antibody, a.a. 305-323

  • Parkin expression profile in dopamine d3 receptor knock-out mice brains. 18612813

    Patients affected by autosomic recessive juvenile parkinsonism (ARJP) exhibit parkin gene mutations with brain decrease in dopamine D2/D3 binding sites. To date, there are no data indicating whether the reduction in dopamine D3 receptors (DRD3) may be associated with the expression of specific parkin variants. In the present study we investigated parkin expression profile in DRD3 knock-out mice brains. RT-PCR analysis was performed to assess qualitative changes in parkin isoforms' distribution pattern and in exons' expression both in wild type controls and dopamine D3 receptor's knock-out mice. Real-time PCR was performed to quantify single exons mRNA. Results demonstrated that exons 1, 2, 4, 6, 7, 8, were more expressed in wild type compared to dopamine D3 receptor KO mice brains while some other (3, 9, 10) were lower expressed. The expression levels of exons 5, 11 and 12 did not change in both animal groups. Our analysis was confirmed by western blot, which showed that parkin protein levels were influenced by the absence of DRD3.
    Document Type:
    Reference
    Product Catalog Number:
    AB5112
    Product Catalog Name:
    Anti-Parkin Antibody, a.a. 305-323

  • Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants. 24473149

    Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (Ret(MEN₂B) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret(MEN₂B) significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD.
    Document Type:
    Reference
    Product Catalog Number:
    AB152
    Product Catalog Name:
    Anti-Tyrosine Hydroxylase Antibody

  • Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration. 25822020

    Parkin and the glial cell line-derived neurotrophic factor (GDNF) receptor RET have both been independently linked to the dopaminergic neuron degeneration that underlies Parkinson's disease (PD). In the present study, we demonstrate that there is genetic crosstalk between parkin and the receptor tyrosine kinase RET in two different mouse models of PD. Mice lacking both parkin and RET exhibited accelerated dopaminergic cell and axonal loss compared with parkin-deficient animals, which showed none, and RET-deficient mice, in which we found moderate degeneration. Transgenic expression of parkin protected the dopaminergic systems of aged RET-deficient mice. Downregulation of either parkin or RET in neuronal cells impaired mitochondrial function and morphology. Parkin expression restored mitochondrial function in GDNF/RET-deficient cells, while GDNF stimulation rescued mitochondrial defects in parkin-deficient cells. In both cases, improved mitochondrial function was the result of activation of the prosurvival NF-κB pathway, which was mediated by RET through the phosphoinositide-3-kinase (PI3K) pathway. Taken together, these observations indicate that parkin and the RET signaling cascade converge to control mitochondrial integrity and thereby properly maintain substantia nigra pars compacta dopaminergic neurons and their innervation in the striatum. The demonstration of crosstalk between parkin and RET highlights the interplay in the protein network that is altered in PD and suggests potential therapeutic targets and strategies to treat PD.
    Document Type:
    Reference
    Product Catalog Number:
    MAB369
    Product Catalog Name:
    Anti-Dopamine Transporter Antibody, NT, clone DAT-Nt
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