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Pesquisa : D12.776.631.050 [Categoria DeCS]
Referências encontradas : 693 [refinar]
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[PMID]:28825343
[Au] Autor:Ohno K; Ohkawara B; Ito M
[Ad] Endereço:a Division of Neurogenetics , Nagoya University Graduate School of Medicine , Nagoya , Japan.
[Ti] Título:Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders.
[So] Source:Expert Opin Ther Targets;21(10):949-958, 2017 Oct.
[Is] ISSN:1744-7631
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, congenital myasthenic syndromes, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Except for sarcopenia, all are orphan diseases. In addition, the NMJ signal transduction is impaired by tetanus, botulinum, curare, α-bungarotoxin, conotoxins, organophosphate, sarin, VX, and soman to name a few. Areas covered: This review covers the agrin-LRP4-MuSK signaling pathway, which drives clustering of acetylcholine receptors (AChRs) and ensures efficient signal transduction at the NMJ. We also address diseases caused by autoantibodies against the NMJ molecules and by germline mutations in genes encoding the NMJ molecules. Expert opinion: Representative small compounds to treat the defective NMJ signal transduction are cholinesterase inhibitors, which exert their effects by increasing the amount of acetylcholine at the synaptic space. Another possible therapeutic strategy to enhance the NMJ signal transduction is to increase the number of AChRs, but no currently available drug has this functionality.
[Mh] Termos MeSH primário: Terapia de Alvo Molecular
Miastenia Gravis/tratamento farmacológico
Doenças Neuromusculares/tratamento farmacológico
[Mh] Termos MeSH secundário: Agrina/metabolismo
Animais
Inibidores da Colinesterase/farmacologia
Desenho de Drogas
Mutação em Linhagem Germinativa
Seres Humanos
Proteínas Relacionadas a Receptor de LDL/metabolismo
Miastenia Gravis/genética
Miastenia Gravis/fisiopatologia
Doenças Neuromusculares/genética
Doenças Neuromusculares/fisiopatologia
Junção Neuromuscular/efeitos dos fármacos
Junção Neuromuscular/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
Receptores Colinérgicos/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Agrin); 0 (Cholinesterase Inhibitors); 0 (LDL-Receptor Related Proteins); 0 (LRP4 protein, human); 0 (Receptors, Cholinergic); EC 2.7.10.1 (MUSK protein, human); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE
[do] DOI:10.1080/14728222.2017.1369960


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[PMID]:28727885
[Au] Autor:Okumura N; Kitahara M; Okuda H; Hashimoto K; Ueda E; Nakahara M; Kinoshita S; Young RD; Quantock AJ; Tourtas T; Schlötzer-Schrehardt U; Kruse F; Koizumi N
[Ad] Endereço:Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
[Ti] Título:Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy.
[So] Source:Invest Ophthalmol Vis Sci;58(9):3697-3707, 2017 Jul 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: The unfolded protein response (UPR) is believed to play a role in the pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this study was to investigate whether unfolded proteins accumulate in the corneal endothelium in FECD and if they are involved in triggering cell death. Methods: Descemet's membranes with corneal endothelial cells (CECs) were obtained during keratoplasty, and expression of aggresomes, type 1 collagen, fibronectin, and agrin was evaluated. Endoplasmic reticulum (ER) stress of immortalized human CECs from non-FECD subjects and from FECD patients (iHCEC and iFECD, respectively) were evaluated. The effect of MG132-mediated aggresome formation on the UPR and intrinsic pathway and the effect of mitochondrial damage on UPR were also examined. The effect of CHOP knockdown on the ER stress-mediated intrinsic pathway was also evaluated. Results: Aggresome formation was higher in iFECD than in iHCEC and was colocalized with type 1 collagen, fibronectin, and agrin. GRP78, phosphorylated IRE1, PERK, and CHOP showed higher activation in iFECD than in iHCEC. MG132-mediated aggresome formation upregulated ER stress sensors, the mitochondrial membrane potential drop, cytochrome c release to the cytoplasm, and activation of caspase-9 and -3. By contrast, staurosporine-mediated mitochondrial damage did not induce ER stress. Knockdown of CHOP attenuated the ER stress-induced cleavage of caspase-9, which is caused by intrinsic pathway activation. Conclusions: Excessive synthesis of extracellular matrix proteins induced unfolded protein accumulation in FECD. Prolonged ER stress-mediated cell death, occurring via the intrinsic apoptotic signaling pathway, therefore might be associated with the pathogenesis of FECD.
[Mh] Termos MeSH primário: Apoptose
Epitélio Posterior/metabolismo
Proteínas da Matriz Extracelular/metabolismo
Distrofia Endotelial de Fuchs/patologia
Agregação Patológica de Proteínas/patologia
Resposta a Proteínas não Dobradas/fisiologia
[Mh] Termos MeSH secundário: Agrina/metabolismo
Células Cultivadas
Colágeno Tipo I/metabolismo
Lâmina Limitante Posterior/metabolismo
Lâmina Limitante Posterior/patologia
Retículo Endoplasmático/metabolismo
Retículo Endoplasmático/patologia
Fibronectinas/metabolismo
Distrofia Endotelial de Fuchs/metabolismo
Proteínas de Choque Térmico/metabolismo
Seres Humanos
Imuno-Histoquímica
Potencial da Membrana Mitocondrial/fisiologia
Meia-Idade
Estresse Oxidativo
Agregação Patológica de Proteínas/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin); 0 (Collagen Type I); 0 (Extracellular Matrix Proteins); 0 (Fibronectins); 0 (Heat-Shock Proteins); 0 (molecular chaperone GRP78)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-21023


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[PMID]:28697334
[Au] Autor:Eroglu E; Chien KR
[Ad] Endereço:Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, SE 171 77.
[Ti] Título:Heart Regeneration 4.0: Matrix Medicine.
[So] Source:Dev Cell;42(1):7-8, 2017 07 10.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The heart has a markedly limited capacity for regeneration. Reporting in Nature, Bassat et al. (2017) and Morikawa et al. (2017) have uncovered a new mechanism of Yap inhibition by the dystrophin glycoprotein complex (DGC) that is released by the extracellular matrix protein Agrin in order to promote cardiac regeneration.
[Mh] Termos MeSH primário: Agrina
Coração
[Mh] Termos MeSH secundário: Membrana Celular
Seres Humanos
Regeneração
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Agrin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE


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[PMID]:28379354
[Au] Autor:Kim JK; Caine C; Awano T; Herbst R; Monani UR
[Ad] Endereço:Department of Pathology and Cell Biology.
[Ti] Título:Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.
[So] Source:Hum Mol Genet;26(13):2377-2385, 2017 Jul 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy.
[Mh] Termos MeSH primário: Agrina/genética
Junção Neuromuscular/metabolismo
[Mh] Termos MeSH secundário: Agrina/metabolismo
Processamento Alternativo
Animais
Modelos Animais de Doenças
Seres Humanos
Camundongos
Camundongos Transgênicos
Neurônios Motores/metabolismo
Fibras Musculares Esqueléticas/metabolismo
Músculo Esquelético/metabolismo
Atrofia Muscular Espinal/genética
Proteínas do Tecido Nervoso/genética
Doenças Neuromusculares/genética
Doenças Neuromusculares/metabolismo
Junção Neuromuscular/genética
Isoformas de Proteínas/genética
Proteína 1 de Sobrevivência do Neurônio Motor/genética
Proteína 2 de Sobrevivência do Neurônio Motor/genética
Sinapses/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin); 0 (Nerve Tissue Proteins); 0 (Protein Isoforms); 0 (Survival of Motor Neuron 1 Protein); 0 (Survival of Motor Neuron 2 Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx124


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[PMID]:28228399
[Au] Autor:Kriz W; Löwen J; Federico G; van den Born J; Gröne E; Gröne HJ
[Ad] Endereço:Department of Neuroanatomy, Medical Faculty Mannheim, University Heidelberg, Germany; wilhelm.kriz@urz.uni-heidelberg.de.
[Ti] Título:Accumulation of worn-out GBM material substantially contributes to mesangial matrix expansion in diabetic nephropathy.
[So] Source:Am J Physiol Renal Physiol;312(6):F1101-F1111, 2017 Jun 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of diabetic nephropathy (DN), generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. Reevaluation of 918 biopsies with DN revealed strong evidence that these mechanisms are connected to each other, wherein excess GBM components fail to undergo degradation and are deposited in the mesangium. These data do not exclude that mesangial cells also synthesize components that contribute to the accumulation of matrix in the mesangium. Light, electron microscopic, immunofluorescence, and in situ hybridization studies clearly show that the thickening of the GBM is due not only to overproduction of components of the mature GBM (α3 and α5 chains of collagen IV and agrin) by podocytes but also to resumed increased synthesis of the α1 chain of collagen IV and of perlecan by endothelial cells usually seen during embryonic development. We hypothesize that these abnormal production mechanisms are caused by different processes: overproduction of mature GBM-components by the diabetic milieu and regression of endothelial cells to an embryonic production mode by decreased availability of mediators from podocytes.
[Mh] Termos MeSH primário: Nefropatias Diabéticas/patologia
Membrana Basal Glomerular/ultraestrutura
Mesângio Glomerular/ultraestrutura
Podócitos/ultraestrutura
[Mh] Termos MeSH secundário: Agrina/análise
Autoantígenos/análise
Biópsia
Microambiente Celular
Colágeno Tipo IV/análise
Nefropatias Diabéticas/metabolismo
Progressão da Doença
Membrana Basal Glomerular/química
Mesângio Glomerular/química
Proteoglicanas de Heparan Sulfato/análise
Seres Humanos
Imuno-Histoquímica
Microscopia Eletrônica de Transmissão
Podócitos/química
Esclerose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin); 0 (Autoantigens); 0 (COL4A1 protein, human); 0 (COL4A5 protein, human); 0 (Collagen Type IV); 0 (Heparan Sulfate Proteoglycans); 0 (type IV collagen alpha3 chain); 143972-95-6 (perlecan)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00020.2017


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[PMID]:28221305
[Au] Autor:Karakaya M; Ceyhan-Birsoy O; Beggs AH; Topaloglu H
[Ad] Endereço:*Pediatric Neurology Unit, Hacettepe University School of Medicine, Ankara, Turkey; and †Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA.
[Ti] Título:A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop.
[So] Source:J Clin Neuromuscul Dis;18(3):147-151, 2017 Mar.
[Is] ISSN:1537-1611
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases of the neuromuscular junction caused by compromised synaptic transmission. Clinical features include early-onset weakness of limbs and oculobulbar muscles resulting in hypotonia, bulbar paresis, ptosis, and hypoventilation. The first dropped head syndrome in children were detected in 2 patients with LMNA and SEPN1 mutations. We report a 17-month-old boy with dropped head and limb-girdle weakness, who had no ptosis or ophthalmoplegia at presentation. We performed whole exome sequencing, which revealed a homozygous missense variant in the AGRN gene c.5023G>A, p.Gly1675Ser in the LG2 domain, which is predicted to be likely disease causing by in silico tools. Agrin is known to play a critical role in the development and maintenance of the neuromuscular junction. Agrin-related CMS is one of the rarest subtypes. Of note, our patient is the first described patient with agrin-related CMS with dropped head phenotype.
[Mh] Termos MeSH primário: Agrina/genética
Mutação de Sentido Incorreto
Síndromes Miastênicas Congênitas/genética
[Mh] Termos MeSH secundário: Pré-Escolar
Análise Mutacional de DNA
Exoma
Seres Humanos
Lactente
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170519
[Lr] Data última revisão:
170519
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170222
[St] Status:MEDLINE
[do] DOI:10.1097/CND.0000000000000132


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[PMID]:28107841
[Au] Autor:Vannoy CH; Zhou H; Qiao C; Xiao X; Bang AG; Lu QL
[Ad] Endereço:McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, North Carolina.
[Ti] Título:Adeno-Associated Virus-Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I.
[So] Source:Am J Pathol;187(2):431-440, 2017 Feb.
[Is] ISSN:1525-2191
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Agrin is a basement membrane-specific proteoglycan that can regulate orientation of cytoskeleton proteins and improve function of dystrophic skeletal muscle. In skeletal muscle, agrin binds with high affinity to laminin(s) and α-dystroglycan (α-DG), an integral part of the dystrophin-glycoprotein complex. Miniaturized forms of agrin (mAgrin) have been shown to ameliorate disease pathology in a laminin-α2 knockout mouse model of muscular dystrophy, acting as a link between α-DG and laminin(s). Here, we test whether mAgrin might also improve pathologies associated with FKRP-related dystroglycanopathies, another form of muscular dystrophy characterized by weak interactions between muscle and basement membranes. We demonstrate in vitro that mAgrin enhances laminin binding to primary myoblasts and fibroblasts from an FKRP mutant mouse model and that this enhancement is abrogated when mAgrin is in molar excess relative to laminin. However, in vivo delivery of mAgrin via adeno-associated virus (AAV) into FKRP mutant mice was unable to improve dystrophic phenotypes, both histologically and functionally. These results likely reflect insufficient binding of mAgrin to hypoglycosylated α-DG on muscle fibers and possibly abrogation of binding from molar excess of overexpressed AAV-delivered mAgrin. Further exploration of mAgrin modification is necessary to strengthen its binding to other membrane components, including hypoglycosylated α-DG, for potential therapeutic applications.
[Mh] Termos MeSH primário: Agrina/genética
Terapia Genética/métodos
Distrofia Muscular Animal/terapia
[Mh] Termos MeSH secundário: Agrina/metabolismo
Animais
Western Blotting
Dependovirus
Imuno-Histoquímica
Laminina/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Músculo Esquelético/metabolismo
Músculo Esquelético/patologia
Distrofia Muscular do Cíngulo dos Membros
Distrofia Muscular Animal/patologia
Fenótipo
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin); 0 (Laminin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170122
[St] Status:MEDLINE


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[PMID]:27756107
[Au] Autor:Rivner MH; Liu S; Quarles B; Fleenor B; Shen C; Pan J; Mei L
[Ad] Endereço:Department of Neurology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA.
[Ti] Título:Agrin and low-density lipoprotein-related receptor protein 4 antibodies in amyotrophic lateral sclerosis patients.
[So] Source:Muscle Nerve;55(3):430-432, 2017 Mar.
[Is] ISSN:1097-4598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The prevalence and characteristics of agrin and low-density lipoprotein-related receptor protein 4 (LRP4) antibody-positive amyotrophic lateral sclerosis (ALS) patients were studied. METHODS: We tested 82 ALS patients and 59 controls for agrin and LRP4 antibodies using enzyme-linked immunoassay (ELISA). RESULTS: We found that 13.8% of ALS patients had agrin antibodies, and 9.8% had LRP4 antibodies. Women with ALS are twice as likely as men to have antibodies. Agrin-positive ALS patients are younger than agrin-negative ALS patients. CONCLUSIONS: Antibodies to agrin and LRP4 are found in ALS patients. It must be determined whether these antibodies are pathogenic. Because antibody-positive patients have upper as well as lower motor neuron findings, the antibodies' effects cannot be explained solely by their actions at the neuromuscular junction. A breakdown in interneuronal signaling may be the cause of ALS. Further research is needed to resolve this question. Muscle Nerve, 2016 Muscle Nerve 55: 430-432, 2017.
[Mh] Termos MeSH primário: Agrina/imunologia
Esclerose Amiotrófica Lateral/sangue
Autoanticorpos/sangue
Lipoproteínas LDL/imunologia
[Mh] Termos MeSH secundário: Fatores Etários
Ensaio de Imunoadsorção Enzimática
Feminino
Seres Humanos
Masculino
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin); 0 (Autoantibodies); 0 (Lipoproteins, LDL)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161019
[St] Status:MEDLINE
[do] DOI:10.1002/mus.25438


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[PMID]:27839998
[Au] Autor:Li L; Cao Y; Wu H; Ye X; Zhu Z; Xing G; Shen C; Barik A; Zhang B; Xie X; Zhi W; Gan L; Su H; Xiong WC; Mei L
[Ad] Endereço:Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
[Ti] Título:Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation.
[So] Source:Neuron;92(5):1007-1019, 2016 Dec 07.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurotransmission is ensured by a high concentration of neurotransmitter receptors at the postsynaptic membrane. This is mediated by scaffold proteins that bridge the receptors with cytoskeleton. One such protein is rapsyn (receptor-associated protein at synapse), which is essential for acetylcholine receptor (AChR) clustering and NMJ (neuromuscular junction) formation. We show that the RING domain of rapsyn contains E3 ligase activity. Mutation of the RING domain that abolishes the enzyme activity inhibits rapsyn- as well as agrin-induced AChR clustering in heterologous and muscle cells. Further biological and genetic studies support a working model where rapsyn, a classic scaffold protein, serves as an E3 ligase to induce AChR clustering and NMJ formation, possibly by regulation of AChR neddylation. This study identifies a previously unappreciated enzymatic function of rapsyn and a role of neddylation in synapse formation, and reveals a potential target of therapeutic intervention for relevant neurological disorders.
[Mh] Termos MeSH primário: Agrina/metabolismo
Citoesqueleto/metabolismo
Fibras Musculares Esqueléticas/metabolismo
Proteínas Musculares/genética
Junção Neuromuscular/metabolismo
Receptores Colinérgicos/metabolismo
Sinapses/metabolismo
[Mh] Termos MeSH secundário: Animais
Camundongos
Proteínas Musculares/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin); 0 (Muscle Proteins); 0 (Receptors, Cholinergic); 0 (peripheral membrane protein 43K); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161115
[St] Status:MEDLINE


  10 / 693 MEDLINE  
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[PMID]:27380275
[Au] Autor:Daryadel A; Haubitz M; Figueiredo M; Steubl D; Roos M; Mäder A; Hettwer S; Wagner CA
[Ad] Endereço:Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
[Ti] Título:The C-Terminal Fragment of Agrin (CAF), a Novel Marker of Renal Function, Is Filtered by the Kidney and Reabsorbed by the Proximal Tubule.
[So] Source:PLoS One;11(7):e0157905, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Agrin, a multidomain proteoglycan and neurotrypsin, a neuronal serine protease, are important for forming (neuromuscular) synapses. Proteolytical activity of neurotrypsin produces a C-terminal fragment of agrin, termed CAF, of approximately 22 kDA molecular size which also circulates in blood. The presence of CAF in urine suggests either glomerular filtration or secretion into urine. Blood levels of CAF have been identified as a potential novel marker of kidney function. Here we describe that several nephron segments in the mouse kidney express agrin and neutrotrypsin in addition to the localization of both protein in the glomerulum. Agrin mRNA and protein was detected in almost all nephron segments and mRNA abundance was highest in the inner medullary collecting duct. Neurotrypsin mRNA was mostly detected in the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the inner medullary collecting duct. Moreover, we show that the proximal tubule absorbs injected recombinant CAF by a process shared with receptor-mediated and fluid phase endocytosis. Co-injection of CAF with recombinant human transferrin, a substrate of the receptor-mediated endocytic pathway as well as with FITC-labelled dextran (10 kDa), a marker of fluid phase endocytosis, showed partial colocalization of CAF with both markers. Further colocalization of CAF with the lysosomal marker cathepsin B suggested degradation of CAF by the lysosome in the proximal tubule. Thus, the murine kidney expresses agrin and neurotrypsin in nephron segments beyond the glomerulum. CAF is filtered by the glomerulum and is reabsorbed by endocytosis by the proximal tubule. Thus, impaired kidney function could impair glomerular clearance of CAF and thereby increase circulating CAF levels.
[Mh] Termos MeSH primário: Agrina/metabolismo
Biomarcadores/metabolismo
Túbulos Renais Proximais/fisiologia
Rim/fisiologia
Fragmentos de Peptídeos/metabolismo
[Mh] Termos MeSH secundário: Agrina/genética
Animais
Biomarcadores/sangue
Biomarcadores/urina
Endocitose
Perfilação da Expressão Gênica/métodos
Taxa de Filtração Glomerular
Seres Humanos
Immunoblotting
Rim/metabolismo
Túbulos Renais Proximais/metabolismo
Alça do Néfron/metabolismo
Alça do Néfron/fisiologia
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microscopia Confocal
Néfrons/metabolismo
Néfrons/fisiologia
Fragmentos de Peptídeos/genética
Proteoglicanas/genética
Proteoglicanas/metabolismo
Proteínas Recombinantes/administração & dosagem
Proteínas Recombinantes/metabolismo
Proteínas Recombinantes/farmacocinética
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Serina Endopeptidases/genética
Serina Endopeptidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agrin); 0 (Biomarkers); 0 (C-terminal agrin fragment); 0 (Peptide Fragments); 0 (Proteoglycans); 0 (Recombinant Proteins); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.- (neurotrypsin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160706
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0157905



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