Cloning of Rat Parkin cDNA and Distribution of Parkin in Rat Brain

Gu, Wen‐Jie; Abbas, Nacer; Lagunes, Martin Zarate; Parent, André; Pradier, Laurent; Böhme, Georg Andrees; Agid, Yves; Hirsch, Étienne C.; Raisman‐Vozari, Rita; Brice, Alexis

doi:10.1046/j.1471-4159.2000.0741773.x

Cited by 42 publications

(13 citation statements)

References 21 publications

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“…Expression studies in mammals demonstrated that, in addition to brain regions, parkin is expressed widely in extracerebral tissues 16,17 and the fact that parkin mRNA is expressed in the bovine PNS 18 supports the contention that this protein also plays a role in the PNS. In bovine peripheral nerve, parkin protein was shown recently to be present at two distinct locations: the axoplasm of the myelinated nerve fibers, and the Schwann cells.…”

Section: Discussionmentioning

confidence: 89%

“…After first-strand cDNA synthesis, the parkin cDNA was co-amplified together with the glyceraldehyde-3-phosphate dehydrogenase (G3PDH) cDNA as an endogenous standard sequence. 17 Two regions of the parkin cDNA were amplified: a first set of primers (forward 5Ј-TTCAACTCCAGCCATGGTTTC-3Ј and reverse 5Ј-CG-TAATGCAAGTGATGTTCCG-3Ј) was designed to span parkin exons 2 to 6 (120 -821 base pairs [bp] of cDNA GenBank accession number AB009973). A second primer set (forward 5Ј-TTAAATGTGGAGCACACCCCA-3Ј and reverse 5Ј-TTT-GGAGGCTGCTTCCCAA-3Ј) was used to amplify parkin exons 6 to 11 (729 -1,325 bp of cDNA, GenBank accession number AB009973).…”

Section: Molecular Analysismentioning

confidence: 99%

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Does parkin play a role in the peripheral nervous system? A family report

et al. 2004

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Two genes were identified for autosomal recessive forms of early onset Parkinson's disease: parkin and DJ-1. We describe 2 siblings with EOPD due to parkin mutations and peripheral neuropathy, which presented as neuropathy with liability to pressure palsies (HNPP) in the index case. RT-PCR experiments revealed that the parkin gene is expressed in sural nerves from both controls and patient with parkin-related disease. Our findings support the view that parkin may play a role in the peripheral nervous system.

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Section: Discussionmentioning

confidence: 89%

Section: Molecular Analysismentioning

confidence: 99%

Does parkin play a role in the peripheral nervous system? A family report

et al. 2004

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“…These findings are similar to the localization of endogenous Parkin reported by others. Although the majority of staining is cytoplasmic (Shimura et al, 1999;Gu et al, 2000;Horowitz et al, 2001), nuclear (Stichel et al, Parkin Inclusion Formation Vol. 14, November 2003 2000; Horowitz et al, 2001), ER (Imai et al, 2002), Golgi (Shimura et al, 1999), trans-Golgi network, and vesicular staining (Kubo et al, 2001) have also been reported.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Proteasomal Activity Causes Inclusion Formation in Neuronal and Non-Neuronal Cells Overexpressing Parkin

Ardley

Scott

Rose

et al. 2003

MBoC

113

137

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Association between protein inclusions and neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, and polyglutamine disorders, has been widely documented. Although ubiquitin is conjugated to many of these aggregated proteins, the 26S proteasome does not efficiently degrade them. Mutations in the ubiquitin-protein ligase Parkin are associated with autosomal recessive juvenile Parkinsonism. Although Parkin-positive inclusions are not detected in brains of autosomal recessive juvenile Parkinsonism patients, Parkin is found in Lewy bodies in sporadic disease. This suggests that loss of Parkin ligase activity via mutation, or sequestration to Lewy bodies, is a contributory factor to sporadic disease onset. We now demonstrate that decreased proteasomal activity causes formation of large, noncytotoxic inclusions within the cytoplasm of both neuronal and nonneuronal cells overexpressing Parkin. This is not a general phenomenon as there is an absence of similar inclusions when HHARI, a structural homolog of Parkin, is overexpressed. The inclusions colocalize with ubiquitin and with proteasomes. Furthermore, Parkin inclusions colocalize with gamma-tubulin, acetylated alpha-tubulin, and cause redistribution of vimentin, suggesting aggresome-like properties. Our data imply that lower proteasomal activity, previously observed in brain tissue of Parkinson's disease patients, leads to Parkin accumulation and a concomitant reduction in ligase activity, thereby promoting Lewy body formation.

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“…GST⅐NR2B was a gift from Dr. David Bredt (UCSF). The parkin antibody ASP5p was described previously (15). The anti-Ubl parkin antibody was raised in rabbit against the GST⅐Ubl fusion protein.…”

Section: Methodsmentioning

confidence: 99%

Parkin and CASK/LIN-2 Associate via a PDZ-mediated Interaction and Are Co-localized in Lipid Rafts and Postsynaptic Densities in Brain

Fallon

Croft

Labib

et al. 2002

Journal of Biological Chemistry

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173

128

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Mutations in the gene encoding parkin cause an autosomal recessive juvenile-onset form of Parkinson's disease. Parkin functions as a RING-type E3 ubiquitin-ligase, coordinating the transfer of ubiquitin to substrate proteins and thereby targeting them for degradation by the proteasome. We now report that the extreme C terminus of parkin, which is selectively truncated by a Parkinson's disease-causing mutation, functions as a class II PDZ-binding motif that binds CASK, the mammalian homolog of Caenorhabditis elegans Lin-2, but not other PDZ proteins in brain extracts. Importantly, parkin co-localizes with CASK at synapses in cultured cortical neurons as well as in postsynaptic densities and lipid rafts in brain. Further, parkin associates not only with CASK but also with other postsynaptic proteins in the N-methyl D-aspartate (NMDA) receptor-signaling complex, in rat brain in vivo. Finally, despite exhibiting E2-dependent ubiquitin ligase activity, rat brain parkin does not ubiquitinate CASK, suggesting that CASK may function in targeting or scaffolding parkin within the postsynaptic complex rather than as a direct substrate for parkin-mediated ubiquitination. These data implicate for the first time a PDZ-mediated interaction between parkin and CASK in neurodegeneration and possibly in ubiquitination of proteins involved in synaptic transmission and plasticity.Parkinson's disease (PD) 1 involves the selective degeneration of midbrain dopamine neurons, resulting in motor abnormalities and progressive disability. Recently, three genes responsible for inherited forms of PD have been identified. Mutations in the genes encoding ␣-synuclein and ubiquitin C-terminal hydrolase L1 (UCH-L1) each cause rare autosomal dominant forms of PD (1, 2). In contrast, mutations in the gene encoding parkin cause an autosomal recessive, juvenile-onset form of PD and account for more cases of PD than all other familial causes combined (3, 4). Further, Lewy bodies, the cytoplasmic inclusions that constitute the pathological hallmark of the disease, contain ␣-synuclein, UCH-L1 and parkin deposits even in sporadic cases, suggesting a broader role for these three genes in PD (2, 5, 6). Interestingly however, Lewy bodies do not occur in the brains of patients with familial PD caused by parkin mutations, implicating parkin in the biogenesis of these inclusions (3).Another major component of Lewy bodies is ubiquitin (Ub), a small protein that can be covalently attached to other proteins (7). Conjugation of Ub onto proteins requires the concerted activity of three enzymes, an E1 Ub-activating enzyme, an E2 Ub-conjugating enzyme, and an E3 Ub-ligase. Ubiquitinated proteins are then targeted for degradation by the 26 S proteasome. The ubiquitin proteasome pathway (UPP) is one of the main pathways for protein degradation and has been implicated in a number of important cellular regulatory processes (8). There is considerable evidence that parkin also functions in the UPP. Indeed, the N terminus of parkin shares homology with ubiquitin (Ub-like dom...

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Cloning of Rat Parkin cDNA and Distribution of Parkin in Rat Brain

Cited by 42 publications

References 21 publications

Does parkin play a role in the peripheral nervous system? A family report

Does parkin play a role in the peripheral nervous system? A family report

Inhibition of Proteasomal Activity Causes Inclusion Formation in Neuronal and Non-Neuronal Cells Overexpressing Parkin

Parkin and CASK/LIN-2 Associate via a PDZ-mediated Interaction and Are Co-localized in Lipid Rafts and Postsynaptic Densities in Brain

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