SEPT5_v2 is a parkin-binding protein

Choi, Peter S.; Snyder, Heather M.; Petrucelli, Leonard; Theisler, Catherine; Chong, Matthew; Zhang, Y.; Lim, Kah‐Leong; Chung, Kenny K.K.; Kehoe, Kathryn; D’Adamio, Luciano; Lee, J.M.; Cochran, Elizabeth J.; Bowser, Rachel K.; Dawson, Ted M.; Wolozin, Benjamin

doi:10.1016/s0169-328x(03)00318-8

Cited by 113 publications

(81 citation statements)

References 35 publications

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“…74 Septins 2 and 4 have previously been associated with Alzheimer's disease due to their localization in neurofibrillary tangles 83 and septin 5 is a known binding partner of the Parkinson's diseaseassociated protein parkin. 84 In addition, a review of the septin family of proteins and their distribution in mouse brains 81 found that the majority of the septin family were localized around synaptic vesicles near the terminals in unmyelinated axons with the highest expression within the brain seen in the cerebral cortex, hippocampus, cerebellum, thalamus and striatum. These data and the other work discussed previously indicate that members of the septin family of proteins may function in synaptic vesicle transport, fusion or recycling events in the human brain.…”

Section: Discussionmentioning

confidence: 99%

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

et al. 2007

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There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P < 0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

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Section: Discussionmentioning

confidence: 99%

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

et al. 2007

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“…Because this function appears to be defective in patients with parkin mutations, the identification of protein substrates is of great importance (6, 10). Parkin substrates include synaptic proteins (the septins CDCrel-1 and CDCrel-2, synaptotagmin XI, and the ␣-synuclein interactor synphilin-1), PaelR (parkin-associated endothelin-like receptor), cyclin E, ␣/␤ tubulin, and the p38 subunit of the aminoacyl-tRNA synthetase complex (9,(11)(12)(13)(14)(15)(16)(17). Parkin expression was found to be neuroprotective in Drosophila (18) and in cell culture models of dopamine neuron loss (19 -22).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Parkin Phosphorylation and Modulation of Its E3 Ubiquitin Ligase Activity

Yamamoto

Friedlein

Imai

et al. 2005

Journal of Biological Chemistry

106

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Mutations in the PARKIN Parkinson's disease (PD)1 is the second most common neurodegenerative disorder. Parkinsonian symptoms are caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (1). Although more than 90% of PD cases occur sporadically, the study of genetic mutations has offered great insight into the molecular mechanisms of PD (2). After the discovery that mutations in the PARKIN gene cause autosomal recessive juvenile parkinsonism (3), parkin mutations have been recognized as the most common cause of hereditary PD and possibly a risk factor for idiopathic PD (4, 5).The PARKIN gene comprises 12 exons and codes for a 465-amino acid protein that is widely expressed, most prominently in muscle and throughout the brain (3). The 52-kDa parkin protein comprises an N-terminal ubiquitin-like domain (aa 1-76), a unique parkin domain (aa 145-232), and two RING (really interesting new gene) fingers (aa 238 -293 and 418 -449, respectively) flanking an IBR (in-between RING) domain (aa 314 -377) at the C terminus. All of these domains appear to be functionally important, because PD mutations cluster in them (6).Parkin functions in the ubiquitin-proteasome system as an E3 ubiquitin-protein ligase together with the E2 ubiquitinconjugating co-enzymes UbcH7 or UbcH8 (7-9). Because this function appears to be defective in patients with parkin mutations, the identification of protein substrates is of great importance (6, 10). Parkin substrates include synaptic proteins (the septins CDCrel-1 and CDCrel-2, synaptotagmin XI, and the ␣-synuclein interactor synphilin-1), PaelR (parkin-associated endothelin-like receptor), cyclin E, ␣/␤ tubulin, and the p38 subunit of the aminoacyl-tRNA synthetase complex (9,(11)(12)(13)(14)(15)(16)(17). Parkin expression was found to be neuroprotective in Drosophila (18) and in cell culture models of dopamine neuron loss (19 -22). However, the exact molecular mechanisms of how parkin dysfunction causes PD remain to be elucidated (6, 10).Post-translational modifications often regulate enzymatic activity. Nitrosylation of parkin was recently found to occur in PD, leading to an inhibition of its ubiquitin ligase activity (23,24). Here we addressed the question whether phosphorylation of parkin occurred and, if so, by which kinases under what cellular conditions. Parkin was found to be phosphorylated on at least five serine residues. Casein kinase-1 (CK-1), protein kinase A (PKA) and protein kinase C (PKC) were identified as parkin kinases in vitro, and inhibition of CK-1 suppressed phosphorylation of parkin in cell lysates. Unfolded protein stress mediated by proteasomal inhibition or endoplasmatic reticulum (ER) stress, but not oxidative stress, reduced the overall phosphorylation of parkin. Unphosphorylated parkin isolated from eukaryotic cells or purified as recombinant fusion protein from bacteria showed a small but significant increase of autoubiquitin ligase activity, compared with parkin phosphorylated in vivo and in vitro. Thus, we suggest that modulat...

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“…S-nitrosylation of parkin inhibits its ubiquitination and protective function (Chung et al, 2004;Yao et al, 2004); thus, accumulation of parkin substrates may also contribute to the neurodegeneration in sporadic PD. A number of parkin substrates have been identified including, CDCrel-1, CDCrel-2, synphilin-1, glycosylated ␣-synuclein, ␤-tubulin, cyclin E, synaptotamin XI (SytXI), parkin-associated endothelin-like receptor (Pael-R), and p38/JTV-1 subunit of the multi-tRNA synthetase complex (Zhang et al, 2000;Chung et al, 2001;Imai et al, 2001;Shimura et al, 2001;Choi et al, 2003;Corti et al, 2003;Huynh et al, 2003;Ren et al, 2003;Staropoli et al, 2003;Jiang et al, 2004). CDCrel-1, CDCrel-2, Pael-R, and cyclin E appear to be upregulated in AR-JP brains (Imai et al, 2001;Choi et al, 2003;Staropoli et al, 2003), but none of these substrates have been reported to be upregulated in parkin knockout (KO) mice.…”

Section: Introductionmentioning

confidence: 99%

“…A number of parkin substrates have been identified including, CDCrel-1, CDCrel-2, synphilin-1, glycosylated ␣-synuclein, ␤-tubulin, cyclin E, synaptotamin XI (SytXI), parkin-associated endothelin-like receptor (Pael-R), and p38/JTV-1 subunit of the multi-tRNA synthetase complex (Zhang et al, 2000;Chung et al, 2001;Imai et al, 2001;Shimura et al, 2001;Choi et al, 2003;Corti et al, 2003;Huynh et al, 2003;Ren et al, 2003;Staropoli et al, 2003;Jiang et al, 2004). CDCrel-1, CDCrel-2, Pael-R, and cyclin E appear to be upregulated in AR-JP brains (Imai et al, 2001;Choi et al, 2003;Staropoli et al, 2003), but none of these substrates have been reported to be upregulated in parkin knockout (KO) mice. Parkin-deficient mice with targeted disruption of parkin exon 3, which have subtle behavioral deficits and enhanced dopamine metabolism without loss of dopaminergic neurons (Goldberg et al, 2003;Itier et al, 2003), surprisingly, showed similar levels of CDCrel-1, synphilin-1, and ␣-synuclein (Goldberg et al, 2003;Palacino et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death

Ko¹,

Coelln²,

Sriram³

et al. 2005

J. Neurosci.

224

197

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Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-␣ treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.

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SEPT5_v2 is a parkin-binding protein

Cited by 113 publications

References 35 publications

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

Parkin Phosphorylation and Modulation of Its E3 Ubiquitin Ligase Activity

Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death

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