Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deletion and point (L166P) mutations of DJ-1 have recently been shown to be responsible for the onset of familial Parkinson's disease (PD, PARK7). The aim of this study was to determine the role of DJ-1 in PD. We first found that DJ-1 eliminated hydrogen peroxide in vitro by oxidizing itself. We then found that DJ-1 knockdown by short interfering RNA rendered SH-SY5Y neuroblastoma cells susceptible to hydrogen peroxide-, MPP+- or 6-hydroxydopamine-induced cell death and that cells harbouring mutant forms of DJ-1, including L166P, became susceptible to death in parallel with the loss of oxidized forms of DJ-1. These results clearly showed that DJ-1 has a role in the antioxidative stress reaction and that mutations of DJ-1 lead to cell death, which is observed in PD.
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PMID:DJ-1 has a role in antioxidative stress to prevent cell death. 1474 23

Mutations in DJ-1 (PARK7) cause recessively inherited Parkinson's disease. DJ-1 is a multifunctional protein with antioxidant and transcription modulatory activity. Its localization in cytoplasm, mitochondria, and nucleus is recognized, but the relevance of this subcellular compartmentalization to its cytoprotective activity is not fully understood. Here we report that under basal conditions DJ-1 is present mostly in the cytoplasm and to a lesser extent in mitochondria and nucleus of dopaminergic neuroblastoma SK-N-BE(2)C cells. Upon oxidant challenge, more DJ-1 translocates to mitochondria within 3 hr and subsequently to the nucleus by 12 hr. The predominant DJ-1 species in both mitochondria and nucleus is a dimer believed to be the functional form. Mutating cysteine 106, 53, or 46 had no impact on the translocation of DJ-1 to mitochondria. To study the relative neuroprotective activity of DJ-1 in mitochondria and nucleus, DJ-1 cDNA constructs fused to the appropriate localization signal were transfected into cells. Compared with 30% protection against oxidant-induced cell death in wild-type DJ-1-transfected cells, mitochondrial targeting of DJ-1 provided a significantly stronger (55%) cytoprotection based on lactate dehydrogenase release. Nuclear targeting of DJ-1 preserved cells equally as well as the wild-type protein. These observations suggest that the time frame for the translocation of DJ-1 from the cytoplasm to mitochondria and to the nucleus following oxidative stress is quite different and that dimerized DJ-1 in mitochondria is functional as an antioxidant not related to cysteine modification. These findings further highlight the multifaceted functions of DJ-1 as a cytoprotector in different cellular compartments.
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PMID:Mitochondrial localization of DJ-1 leads to enhanced neuroprotection. 1871 45

Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)- and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration.
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PMID:Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations. 1902 31

Mutations in PARK7/DJ-1 gene are associated to autosomal recessive early onset forms of Parkinson's disease (PD). Although large gene deletions have been linked to a loss-of-function phenotype, the pathogenic mechanism of missense mutations is less clear. The L166P mutation causes misfolding of DJ-1 protein and its degradation. L166P protein may also accumulate into insoluble cytoplasmic aggregates with a mechanism facilitated by the E3 ligase TNF receptor associated factor 6 (TRAF6). Upon proteasome impairment L166P activates the JNK/p38 MAPK apoptotic pathway by its interaction with TRAF and TNF Receptor Associated Protein (TTRAP). When proteasome activity is blocked in the presence of wild-type DJ-1, TTRAP forms aggregates that are localized to the cytoplasm or associated to nucleolar cavities, where it is required for a correct rRNA biogenesis. In this study we show that in post-mortem brains of sporadic PD patients TTRAP is associated to the nucleolus and to Lewy Bodies, cytoplasmic aggregates considered the hallmark of the disease. In SH-SY5Y neuroblastoma cells, misfolded mutant DJ-1 L166P alters rRNA biogenesis inhibiting TTRAP localization to the nucleolus and enhancing its recruitment into cytoplasmic aggregates with a mechanism that depends in part on TRAF6 activity. This work suggests that TTRAP plays a role in the molecular mechanisms of both sporadic and familial PD. Furthermore, it unveils the existence of an interplay between cytoplasmic and nucleolar aggregates that impacts rRNA biogenesis and involves TRAF6.
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PMID:Parkinson's disease DJ-1 L166P alters rRNA biogenesis by exclusion of TTRAP from the nucleolus and sequestration into cytoplasmic aggregates via TRAF6. 2253 38

DJ-1/PARK7 has multiple functions as an antioxidant, an oncogene, and a molecular chaperone in vertebrates, and loss-of-function mutations in DJ-1 cause early onset of Parkinson's disease. However, the function of invertebrate DJ-1 remains unknown. In order to investigate the function of planarian DJ-1, we isolated the planarian DJ-1 gene Dugesia japonica DJ-1 (DjDJ-1) and analyzed its expression and function. In situ hybridization analysis revealed that DjDJ-1 mRNA was expressed throughout the body, including the central nervous system, cells surrounding the pharynx, and stem cells. Planarian DjDJ-1 protein exhibited antioxidant function, similar to human DJ-1, as evidenced by the fact that recombinant DjDJ-1 protein reduced reactive oxygen species and protected human neuroblastoma SH-SY5Y cells from cell death. In addition, dopaminergic neurons in DjDJ-1(RNAi) planarians became susceptible to 6-hydroxydopamine, a dopaminergic neurotoxin. These results suggest that planarians have a DJ-1 ortholog, which has conserved antioxidant and neuroprotective functions.
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PMID:Protective effect of planarian DJ-1 against 6-hydroxydopamine-induced neurotoxicity. 2302 78

Astrocytes are the most abundant glial cell type in the brain. Impairment in astrocyte functions can critically influence neuronal survival and leads to neurodegeneration. Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor dysfunction that results from progressive neuronal loss. Astrocytic dysfunction was demonstrated in human samples and in experimental models of PD. Mutations in DJ-1 (PARK7) leading to loss of functional protein cause familial PD and enhance sensitivity to oxidative insults. Recently, an increase in DJ-1's expression was found in reactive astrocytes in various neurodegenerative disorders. Here we show that lack of DJ-1 attenuates astrocytes' ability to support neuronal cells, thereby leading to accelerated neuronal damage. DJ-1 knockout mice demonstrated increased vulnerability in vivo to 6-hydroxydopamine (6-OHDA) hemiparkinsonian PD model. Astrocytes isolated from DJ-1 knockout mice showed an inferior ability to protect human neuroblastoma cells against 6-OHDA insult both by co-culture and through their conditioned media, as compared to wild-type astrocytes. DJ-1 knockout astrocytes showed blunted ability to increase the expression of cellular protective mechanisms against oxidative stress mediated via Nrf-2 and HO-1 in response to exposure to 6-OHDA. These experiments demonstrated that lack of DJ-1 impairs astrocyte-mediated neuroprotection.
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PMID:Knocking out DJ-1 attenuates astrocytes neuroprotection against 6-hydroxydopamine toxicity. 2353 31

Nuclear respiratory factor 1 (NRF1) serves as a transcription factor that activates the expression of a wide range of nuclear genes essential for mitochondrial biogenesis and function, including mitochondrial respiratory complex subunits, heme biosynthetic enzymes, and regulatory factors involved in the replication and transcription of mitochondrial DNA. Increasing evidence indicates that mitochondrial function is severely compromised in the brains of aging-related neurodegenerative diseases. To identify the comprehensive set of human NRF1 target genes potentially relevant to the pathogenesis of neurodegenerative diseases, we analyzed the NRF1 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset retrieved from the Encyclopedia of DNA Elements (ENCODE) project. Overall, we identified 2,470 highly stringent ChIP-Seq peaks on protein-coding genes in SK-N-SH human neuroblastoma cells. They were accumulated in the proximal promoter regions with an existence of the NRF1-binding consensus sequence. The set of ChIP-Seq-based NRF1 target genes included known NRF1 targets such as EIF2S1, EIF2S2, CYCS, FMR1, FXR2, E2F6, CD47, and TOMM34. By pathway analysis, the molecules located in the core pathways related to mitochondrial respiratory function were determined to be highly enriched in NRF1 target genes. Furthermore, we found that NRF1 target genes play a pivotal role in regulation of extra-mitochondrial biological processes, including RNA metabolism, splicing, cell cycle, DNA damage repair, protein translation initiation, and ubiquitin-mediated protein degradation. We identified a panel of neurodegenerative disease-related genes, such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) for Parkinson's disease, as well as PSENEN (Pen2) and MAPT (tau) for Alzheimer's disease, as previously unrecognized NRF1 targets. These results suggest a logical hypothesis that aberrant regulation of NRF1 and its targets might contribute to the pathogenesis of human neurodegenerative diseases via perturbation of diverse mitochondrial and extra-mitochondrial functions.
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PMID:Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases. 2425 Feb 22

Ataxin-2 (ATXN2) polyglutamine domain expansions of large size result in an autosomal dominantly inherited multi-system-atrophy of the nervous system named spinocerebellar ataxia type 2 (SCA2), while expansions of intermediate size act as polygenic risk factors for motor neuron disease (ALS and FTLD) and perhaps also for Levodopa-responsive Parkinson's disease (PD). In view of the established role of ATXN2 for RNA processing in periods of cell stress and the expression of ATXN2 in blood cells such as platelets, we investigated whether global deep RNA sequencing of whole blood from SCA2 patients identifies a molecular profile which might serve as diagnostic biomarker. The bioinformatic analysis of SCA2 blood global transcriptomics revealed various significant effects on RNA processing pathways, as well as the pathways of Huntington's disease and PD where mitochondrial dysfunction is crucial. Notably, an induction of PINK1 and PARK7 expression was observed. Conversely, expression of Pink1 was severely decreased upon global transcriptome profiling of Atxn2-knockout mouse cerebellum and liver, in parallel to strong effects on Opa1 and Ghitm, which encode known mitochondrial dynamics regulators. These results were validated by quantitative PCR and immunoblots. Starvation stress of human SH-SY5Y neuroblastoma cells led to a transcriptional phasic induction of ATXN2 in parallel to PINK1, and the knockdown of one enhanced the expression of the other during stress response. These findings suggest that ATXN2 may modify the known PINK1 roles for mitochondrial quality control and autophagy during cell stress. Given that PINK1 is responsible for autosomal recessive juvenile PD, this genetic interaction provides a concept how the degeneration of nigrostriatal dopaminergic neurons and the Parkinson phenotype may be triggered by ATXN2 mutations.
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PMID:Search for SCA2 blood RNA biomarkers highlights Ataxin-2 as strong modifier of the mitochondrial factor PINK1 levels. 2759 28

DJ-1 is an oxidation sensitive protein encoded by the PARK7 gene. Mutations in PARK7 are a rare cause of familial recessive Parkinson's disease (PD), but growing evidence suggests involvement of DJ-1 in idiopathic PD. The key clinical features of PD, rigidity and bradykinesia, result from neurotransmitter imbalance, particularly the catecholamines dopamine (DA) and noradrenaline. We report in human brain and human SH-SY5Y neuroblastoma cell lines that DJ-1 predominantly forms high molecular weight (HMW) complexes that included RNA metabolism proteins hnRNPA1 and PABP1 and the glycolysis enzyme GAPDH. In cell culture models the oxidation status of DJ-1 determined the specific complex composition. RNA sequencing indicated that oxidative changes to DJ-1 were concomitant with changes in mRNA transcripts mainly involved in catecholamine metabolism. Importantly, loss of DJ-1 function upon knock down (KD) or expression of the PD associated form L166P resulted in the absence of HMW DJ-1 complexes. In the KD model, the absence of DJ-1 complexes was accompanied by impairment in catecholamine homeostasis, with significant increases in intracellular DA and noraderenaline levels. These changes in catecholamines could be rescued by re-expression of DJ-1. This catecholamine imbalance may contribute to the particular vulnerability of dopaminergic and noradrenergic neurons to neurodegeneration in PARK7-related PD. Notably, oxidised DJ-1 was significantly decreased in idiopathic PD brain, suggesting altered complex function may also play a role in the more common sporadic form of the disease.
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PMID:DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis. 2930 79

PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear. In the present study, we found that PARK7 secretion was increased by treatment with 6-OHDA via the unconventional secretory pathway in human neuroblastoma SH-SY5Y cells and MEF cells. We also found that 6-OHDA-induced PARK7 secretion was suppressed in Atg5-, Atg9-, or Atg16l1-deficient MEF cells or ATG16L1 knockdown SH-SY5Y cells, indicating that the autophagy-based unconventional secretory pathway is involved in PARK7 secretion. We moreover observed that 6-OHDA-derived electrophilic quinone induced oxidative stress as indicated by a decrease in glutathione levels, and that this was suppressed by pretreatment with antioxidant NAC. We further found that NAC treatment suppressed autophagy and PARK7 secretion. We also observed that 6-OHDA-induced autophagy was associated with activation of AMPK and ULK1 via a pathway which was independent of MTOR. Collectively these results suggest that electrophilic 6-OHDA quinone enhances oxidative stress, and that this is followed by AMPK-ULK1 pathway activation and induction of secretory autophagy to produce unconventional secretion of PARK7.
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PMID:6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway. 3011 66


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