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Pesquisa : D08.811.277.040.330.300.400.400.100 [Categoria DeCS]
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[PMID]:29289693
[Au] Autor:Wang TY; Ma Z; Wang C; Liu C; Yan DY; Deng Y; Liu W; Xu ZF; Xu B
[Ad] Endereço:Department of Environmental Health, School of Public Health, China Medical University, People's Republic of China.
[Ti] Título:Manganese-induced alpha-synuclein overexpression impairs synaptic vesicle fusion by disrupting the Rab3 cycle in primary cultured neurons.
[So] Source:Toxicol Lett;285:34-42, 2018 Mar 15.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Overexposure to Manganese (Mn) has been known to disrupt neurotransmitter release in the brain. However, the underlying mechanisms of Mn exposure on neurotransmitter vesicle release are still unclear. The current study investigated whether Mn-induced alpha-synuclein protein overexpression could disrupt the Rab3 cycle leading to synaptic vesicle fusion dysfunction. After the neurons were exposed to Mn (100 µM) for 0, 6, 12, 24 h, [Ca ] , alpha-synuclein and Rab3A-GTP protein expression increased gradually. However, the interaction of synaptotagmin/Rab3-GAP and Rab3A-GTP/Rab3-GAP decreased significantly in response to Mn treatment for 12-24 h. Remarkably, the treatment with Mn caused an increase in the interaction of alpha-synuclein/Rab3A-GTP. To further validate that Mn-induced alpha-synuclein disrupted the proteins interactions of Rab3A-GTP/Rab3-GAP, the lentivirus vector of alpha-synuclein/negative shRNA was transfected in primary cultured neurons to knockdown the expression of alpha-synuclein. Our results showed that the interaction of Rab3A-GTP/Rab3-GAP in alpha-synuclein knockdown neurons treated with Mn for 24 h had a significant recovery. These results suggested that Mn-induced alpha-synuclein protein overexpression, which bound to Rab3A-GTP and inhibited the GTP hydrolysis of Rab3 protein, disrupted the Rab3 cycle leading to synaptic vesicle fusion dysfunction.
[Mh] Termos MeSH primário: Manganês/toxicidade
Fusão de Membrana/efeitos dos fármacos
Neurônios/efeitos dos fármacos
Vesículas Sinápticas/efeitos dos fármacos
alfa-Sinucleína/metabolismo
Proteínas rab3 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Técnicas de Silenciamento de Genes
Neurônios/metabolismo
Cultura Primária de Células
Ratos Wistar
Vesículas Sinápticas/metabolismo
alfa-Sinucleína/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (alpha-Synuclein); 42Z2K6ZL8P (Manganese); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


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[PMID]:29348419
[Au] Autor:Wentzel C; Delvendahl I; Sydlik S; Georgiev O; Müller M
[Ad] Endereço:Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
[Ti] Título:Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles.
[So] Source:Nat Commun;9(1):267, 2018 01 18.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Here we explore the relationship between presynaptic homeostatic plasticity and proteasome function at the Drosophila neuromuscular junction. First, we demonstrate that the induction of homeostatic plasticity is blocked after presynaptic proteasome perturbation. Proteasome inhibition potentiates release under baseline conditions but not during homeostatic plasticity, suggesting that proteasomal degradation and homeostatic plasticity modulate a common pool of vesicles. The vesicles that are regulated by proteasome function and recruited during homeostatic plasticity are highly EGTA sensitive, implying looser Ca influx-release coupling. Similar to homeostatic plasticity, proteasome perturbation enhances presynaptic Ca influx, readily-releasable vesicle pool size, and does not potentiate release after loss of specific homeostatic plasticity genes, including the schizophrenia-susceptibility gene dysbindin. Finally, we provide genetic evidence that Dysbindin levels regulate the access to EGTA-sensitive vesicles. Together, our data suggest that presynaptic protein degradation opposes the release of low-release probability vesicles that are potentiated during homeostatic plasticity and whose access is controlled by dysbindin.
[Mh] Termos MeSH primário: Disbindina/metabolismo
Junção Neuromuscular/metabolismo
Plasticidade Neuronal
Complexo de Endopeptidases do Proteassoma/metabolismo
Vesículas Sinápticas/fisiologia
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Cálcio/metabolismo
Drosophila
Proteínas de Drosophila/metabolismo
Ácido Egtázico
Homeostase
Proteínas rab3 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Dysbindin); 0 (RIM protein, Drosophila); 526U7A2651 (Egtazic Acid); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.6.5.2 (rab3 GTP-Binding Proteins); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02494-0


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[PMID]:28803726
[Au] Autor:Solis GP; Bilousov O; Koval A; Lüchtenborg AM; Lin C; Katanaev VL
[Ad] Endereço:Department of Pharmacology and Toxicology, University of Lausanne, CH-1011 Lausanne, Switzerland. Electronic address: gonzalo.solis@unil.ch.
[Ti] Título:Golgi-Resident Gαo Promotes Protrusive Membrane Dynamics.
[So] Source:Cell;170(5):939-955.e24, 2017 Aug 24.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To form protrusions like neurites, cells must coordinate their induction and growth. The first requires cytoskeletal rearrangements at the plasma membrane (PM), the second requires directed material delivery from cell's insides. We find that the Gαo-subunit of heterotrimeric G proteins localizes dually to PM and Golgi across phyla and cell types. The PM pool of Gαo induces, and the Golgi pool feeds, the growing protrusions by stimulated trafficking. Golgi-residing KDELR binds and activates monomeric Gαo, atypically for G protein-coupled receptors that normally act on heterotrimeric G proteins. Through multidimensional screenings identifying > 250 Gαo interactors, we pinpoint several basic cellular activities, including vesicular trafficking, as being regulated by Gαo. We further find small Golgi-residing GTPases Rab1 and Rab3 as direct effectors of Gαo. This KDELR → Gαo → Rab1/3 signaling axis is conserved from insects to mammals and controls material delivery from Golgi to PM in various cells and tissues.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Extensões da Superfície Celular/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
Complexo de Golgi/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Drosophila
Feminino
GTP Fosfo-Hidrolases/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Neuritos/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
Receptores de Peptídeos/metabolismo
Técnicas do Sistema de Duplo-Híbrido
Proteínas rab1 de Ligação ao GTP/metabolismo
Proteínas rab3 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (Receptors, Peptide); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); EC 3.6.5.2 (rab1 GTP-Binding Proteins); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


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[PMID]:28575017
[Au] Autor:Rasnitsyn A; Doucette L; Seifi M; Footz T; Raymond V; Walter MA
[Ad] Endereço:Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
[Ti] Título:FOXC1 modulates MYOC secretion through regulation of the exocytic proteins RAB3GAP1, RAB3GAP2 and SNAP25.
[So] Source:PLoS One;12(6):e0178518, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The neurodegenerative disease glaucoma is one of the leading causes of blindness in the world. Glaucoma is characterized by progressive visual field loss caused by retinal ganglion cell (RGC) death. Both surgical glaucoma treatments and medications are available, however, they only halt glaucoma progression and are unable to reverse damage. Furthermore, many patients do not respond well to treatments. It is therefore important to better understand the mechanisms involved in glaucoma pathogenesis. Patients with Axenfeld-Rieger syndrome (ARS) offer important insight into glaucoma progression. ARS patients are at 50% risk of developing early onset glaucoma and respond poorly to treatments, even when surgical treatments are combined with medications. Mutations in the transcription factor FOXC1 cause ARS. Alterations in FOXC1 levels cause ocular malformations and disrupt stress response in ocular tissues, thereby contributing to glaucoma progression. In this study, using biochemical and molecular techniques, we show that FOXC1 regulates the expression of RAB3GAP1, RAB3GAP2 and SNAP25, three genes with central roles in both exocytosis and endocytosis, responsible for extracellular trafficking. FOXC1 positively regulates RAB3GAP1 and RAB3GAP2, while either increase or decrease in FOXC1 levels beyond its normal range results in decreased SNAP25. In addition, we found that FOXC1 regulation of RAB3GAP1, RAB3GAP2 and SNAP25 affects secretion of Myocilin (MYOC), a protein associated with juvenile onset glaucoma and steroid-induced glaucoma. The present work reveals that FOXC1 is an important regulator of exocytosis and establishes a new link between FOXC1 and MYOC-associated glaucoma.
[Mh] Termos MeSH primário: Proteínas do Citoesqueleto/secreção
Exocitose
Proteínas do Olho/secreção
Fatores de Transcrição Forkhead/fisiologia
Glicoproteínas/secreção
Proteína 25 Associada a Sinaptossoma/fisiologia
Proteínas rab3 de Ligação ao GTP/fisiologia
[Mh] Termos MeSH secundário: Fatores de Transcrição Forkhead/genética
Técnicas de Silenciamento de Genes
Células HeLa
Seres Humanos
Luciferases/genética
RNA Mensageiro/genética
Proteína 25 Associada a Sinaptossoma/genética
Ativação Transcricional
Proteínas rab3 de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytoskeletal Proteins); 0 (Eye Proteins); 0 (FOXC1 protein, human); 0 (Forkhead Transcription Factors); 0 (Glycoproteins); 0 (RAB3GAP2 protein, human); 0 (RNA, Messenger); 0 (SNAP25 protein, human); 0 (Synaptosomal-Associated Protein 25); 0 (trabecular meshwork-induced glucocorticoid response protein); EC 1.13.12.- (Luciferases); EC 3.6.5.2 (RAB3GAP1 protein, human); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178518


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[PMID]:28342870
[Au] Autor:Feldmann A; Bekbulat F; Huesmann H; Ulbrich S; Tatzelt J; Behl C; Kern A
[Ad] Endereço:Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, 55099 Mainz, Germany. Electronic address: afeldman@uni-mainz.de.
[Ti] Título:The RAB GTPase RAB18 modulates macroautophagy and proteostasis.
[So] Source:Biochem Biophys Res Commun;486(3):738-743, 2017 May 06.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Macroautophagy is a conserved degradative pathway and its deterioration is linked to disturbances in cellular proteostasis and multiple diseases. Here, we show that the RAB GTPase RAB18 modulates autophagy in primary human fibroblasts. The knockdown of RAB18 results in a decreased autophagic activity, while its overexpression enhances the degradative pathway. Importantly, this function of RAB18 is dependent on RAB3GAP1 and RAB3GAP2, which might act as RAB GEFs and stimulate the activity of the RAB GTPase. Moreover, the knockdown of RAB18 deteriorates proteostasis and results in the intracellular accumulation of ubiquitinated degradation-prone proteins. Thus, the RAB GTPase RAB18 is a positive modulator of autophagy and is relevant for the maintenance of cellular proteostasis.
[Mh] Termos MeSH primário: Autofagia/genética
Fibroblastos/metabolismo
Proteínas rab de Ligação ao GTP/genética
Proteínas rab3 de Ligação ao GTP/genética
[Mh] Termos MeSH secundário: Fibroblastos/citologia
Regulação da Expressão Gênica
Genes Reporter
Seres Humanos
Proteínas Luminescentes/genética
Proteínas Luminescentes/metabolismo
Cultura Primária de Células
Estabilidade Proteica
Proteólise
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Transdução de Sinais
Proteínas rab de Ligação ao GTP/antagonistas & inibidores
Proteínas rab de Ligação ao GTP/metabolismo
Proteínas rab3 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Luminescent Proteins); 0 (RAB18 protein, human); 0 (RAB3GAP2 protein, human); 0 (RNA, Small Interfering); 0 (Recombinant Fusion Proteins); 0 (red fluorescent protein); EC 3.6.5.2 (RAB3GAP1 protein, human); EC 3.6.5.2 (rab GTP-Binding Proteins); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170327
[St] Status:MEDLINE


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[PMID]:28264913
[Au] Autor:Kawabe H; Mitkovski M; Kaeser PS; Hirrlinger J; Opazo F; Nestvogel D; Kalla S; Fejtova A; Verrier SE; Bungers SR; Cooper BH; Varoqueaux F; Wang Y; Nehring RB; Gundelfinger ED; Rosenmund C; Rizzoli SO; Südhof TC; Rhee JS; Brose N
[Ad] Endereço:Department of Molecular Neurobiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
[Ti] Título:ELKS1 localizes the synaptic vesicle priming protein bMunc13-2 to a specific subset of active zones.
[So] Source:J Cell Biol;216(4):1143-1161, 2017 Apr 03.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Presynaptic active zones (AZs) are unique subcellular structures at neuronal synapses, which contain a network of specific proteins that control synaptic vesicle (SV) tethering, priming, and fusion. Munc13s are core AZ proteins with an essential function in SV priming. In hippocampal neurons, two different Munc13s-Munc13-1 and bMunc13-2-mediate opposite forms of presynaptic short-term plasticity and thus differentially affect neuronal network characteristics. We found that most presynapses of cortical and hippocampal neurons contain only Munc13-1, whereas ∼10% contain both Munc13-1 and bMunc13-2. Whereas the presynaptic recruitment and activation of Munc13-1 depends on Rab3-interacting proteins (RIMs), we demonstrate here that bMunc13-2 is recruited to synapses by the AZ protein ELKS1, but not ELKS2, and that this recruitment determines basal SV priming and short-term plasticity. Thus, synapse-specific interactions of different Munc13 isoforms with ELKS1 or RIMs are key determinants of the molecular and functional heterogeneity of presynaptic AZs.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Sinapses/metabolismo
Vesículas Sinápticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Hipocampo/metabolismo
Camundongos
Neurônios/metabolismo
Isoformas de Proteínas/metabolismo
Transmissão Sináptica/fisiologia
Proteínas rab3 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Intracellular Signaling Peptides and Proteins); 0 (Nerve Tissue Proteins); 0 (Protein Isoforms); 0 (Unc13b protein, mouse); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201606086


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[PMID]:27998991
[Au] Autor:Bruckner JJ; Zhan H; Gratz SJ; Rao M; Ukken F; Zilberg G; O'Connor-Giles KM
[Ad] Endereço:Cell and Molecular Biology Training Program, University of Wisconsin-Madison, Madison, WI 53706.
[Ti] Título:Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release.
[So] Source:J Cell Biol;216(1):231-246, 2017 Jan 02.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The strength of synaptic connections varies significantly and is a key determinant of communication within neural circuits. Mechanistic insight into presynaptic factors that establish and modulate neurotransmitter release properties is crucial to understanding synapse strength, circuit function, and neural plasticity. We previously identified Drosophila Piccolo-RIM-related Fife, which regulates neurotransmission and motor behavior through an unknown mechanism. Here, we demonstrate that Fife localizes and interacts with RIM at the active zone cytomatrix to promote neurotransmitter release. Loss of Fife results in the severe disruption of active zone cytomatrix architecture and molecular organization. Through electron tomographic and electrophysiological studies, we find a decrease in the accumulation of release-ready synaptic vesicles and their release probability caused by impaired coupling to Ca channels. Finally, we find that Fife is essential for the homeostatic modulation of neurotransmission. We propose that Fife organizes active zones to create synaptic vesicle release sites within nanometer distance of Ca channel clusters for reliable and modifiable neurotransmitter release.
[Mh] Termos MeSH primário: Canais de Cálcio/metabolismo
Proteínas do Citoesqueleto/metabolismo
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Terminações Pré-Sinápticas/metabolismo
Transmissão Sináptica
Vesículas Sinápticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio/genética
Sinalização do Cálcio
Proteínas do Citoesqueleto/genética
Proteínas de Drosophila/genética
Drosophila melanogaster/genética
Drosophila melanogaster/ultraestrutura
Tomografia com Microscopia Eletrônica
Genótipo
Masculino
Microscopia Confocal
Microscopia Eletrônica de Transmissão
Mutação
Proteínas do Tecido Nervoso/genética
Plasticidade Neuronal
Fenótipo
Ligação Proteica
Potenciais Sinápticos
Vesículas Sinápticas/genética
Proteínas rab3 de Ligação ao GTP/genética
Proteínas rab3 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Calcium Channels); 0 (Cytoskeletal Proteins); 0 (Drosophila Proteins); 0 (Fife protein, Drosophila); 0 (Nerve Tissue Proteins); 0 (RIM protein, Drosophila); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201601098


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[PMID]:27869814
[Au] Autor:Franke C; Sauer M; van de Linde S
[Ad] Endereço:Department of Biotechnology and Biophysics, University of Würzburg, Würzburg, Germany.
[Ti] Título:Photometry unlocks 3D information from 2D localization microscopy data.
[So] Source:Nat Methods;14(1):41-44, 2017 Jan.
[Is] ISSN:1548-7105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We developed a straightforward photometric method, temporal, radial-aperture-based intensity estimation (TRABI), that allows users to extract 3D information from existing 2D localization microscopy data. TRABI uses the accurate determination of photon numbers in different regions of the emission pattern of single emitters to generate a z-dependent photometric parameter. This method can determine fluorophore positions up to 600 nm from the focal plane and can be combined with biplane detection to further improve axial localization.
[Mh] Termos MeSH primário: Imagem Tridimensional/métodos
Microscopia/métodos
Imagem Molecular/métodos
Fotometria/métodos
Soroalbumina Bovina/metabolismo
Proteínas rab3 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Algoritmos
Animais
Bovinos
Simulação por Computador
Seres Humanos
Fótons
Análise de Célula Única/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
27432CM55Q (Serum Albumin, Bovine); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161122
[St] Status:MEDLINE
[do] DOI:10.1038/nmeth.4073


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[PMID]:27664330
[Au] Autor:Wang L; Skotland T; Berge V; Sandvig K; Llorente A
[Ad] Endereço:Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
[Ti] Título:Exosomal proteins as prostate cancer biomarkers in urine: From mass spectrometry discovery to immunoassay-based validation.
[So] Source:Eur J Pharm Sci;98:80-85, 2017 Feb 15.
[Is] ISSN:1879-0720
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumor-specific molecules can be found in exosomes isolated from biological fluids. We have previously analyzed the proteome of urinary exosomes by mass spectrometry, and identified proteins differentially expressed in prostate cancer patients compared to healthy males. Since mass spectrometry is so far not commonly used in clinical laboratories, we have here investigated whether antibody-based methods such as Western blot or ELISA can be used to validate the use of the identified proteins as prostate cancer biomarkers. Western blot experiments designed to detect flotillin 2, TMEM256, Rab3B and LAMTOR1 showed that the level of these proteins was higher in urinary exosomes from prostate cancer patients compared to healthy males. Furthermore, a receiver operating characteristic curve of flotillin 2 in samples from 16 controls and 16 patients showed an area under the curve of 0.91, and 88% sensitivity at a threshold set to give 94% specificity. In addition, ELISA-based detection of flotillin 2 and PARK7 showed that the combination of these proteins was able to distinguish prostate cancer patients and healthy controls with 68% sensitivity and 93% specificity. Several promising biomarkers identified by mass spectrometry could not be evaluated by Western blot or ELISA due to their low exosomal amount and/or lack of good antibodies. In conclusion, our results show that several urinary exosomal proteins identified as prostate cancer biomarkers by mass spectrometry have a high diagnostic value also when analyzed by immunology-based methods, thus bringing these biomarkers closer to a potential clinical use.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/metabolismo
Exossomos/metabolismo
Neoplasias da Próstata/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Proteínas de Transporte/metabolismo
Seres Humanos
Imunoensaio
Masculino
Espectrometria de Massas
Proteínas de Membrana/metabolismo
Meia-Idade
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
Proteínas rab3 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Carrier Proteins); 0 (Membrane Proteins); 0 (TMEM26 protein, human); 0 (flotillins); 0 (p27RF-Rho protein, human); EC 3.6.1.- (RAB3B protein, human); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160925
[St] Status:MEDLINE


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[PMID]:27794539
[Au] Autor:Islam MS; Nolte H; Jacob W; Ziegler AB; Pütz S; Grosjean Y; Szczepanowska K; Trifunovic A; Braun T; Heumann H; Heumann R; Hovemann B; Moore DJ; Krüger M
[Ad] Endereço:Silantes GmbH, Munich, Germany.
[Ti] Título:Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease.
[So] Source:Hum Mol Genet;25(24):5365-5382, 2016 Dec 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinson`s disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model. To explore the function of LRRK2 variants in vivo, we performed mass spectrometry and quantified 3,616 proteins in the fly brain. We identify several differentially-expressed cytoskeletal, mitochondrial and synaptic vesicle proteins (SV), including synaptotagmin-1, syntaxin-1A and Rab3, in the brain of this LRRK2 fly model. In addition, a global phosphoproteome analysis reveals the enhanced phosphorylation of several SV proteins, including synaptojanin-1 (pThr1131) and the microtubule-associated protein futsch (pSer4106) in the brain of R1441C hLRRK2 flies. The direct phosphorylation of human synaptojanin-1 by R1441C hLRRK2 could further be confirmed by in vitro kinase assays. A protein-protein interaction screen in the fly brain confirms that LRRK2 robustly interacts with numerous SV proteins, including synaptojanin-1 and EndophilinA. Our proteomic, phosphoproteomic and interactome study in the Drosophila brain provides a systematic analyses of R1441C hLRRK2-induced pathobiological mechanisms in this model. We demonstrate for the first time that the R1441C mutation located within the LRRK2 GTPase domain induces the enhanced phosphorylation of SV proteins in the brain.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Neurônios Dopaminérgicos/metabolismo
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética
Doença de Parkinson/genética
Proteoma/genética
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Encéfalo/patologia
Modelos Animais de Doenças
Neurônios Dopaminérgicos/patologia
Proteínas de Drosophila/biossíntese
Proteínas de Drosophila/genética
Drosophila melanogaster/genética
Drosophila melanogaster/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/biossíntese
Mutação
Proteínas do Tecido Nervoso/biossíntese
Proteínas do Tecido Nervoso/genética
Doença de Parkinson/metabolismo
Doença de Parkinson/patologia
Monoéster Fosfórico Hidrolases/biossíntese
Monoéster Fosfórico Hidrolases/genética
Fosforilação
Mapas de Interação de Proteínas
Vesículas Sinápticas/genética
Sinaptotagmina I/biossíntese
Sinaptotagmina I/genética
Sintaxina 1/biossíntese
Sintaxina 1/genética
Proteínas rab3 de Ligação ao GTP/biossíntese
Proteínas rab3 de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Nerve Tissue Proteins); 0 (Proteome); 0 (Synaptotagmin I); 0 (Syntaxin 1); EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2); EC 3.1.3.- (synaptojanin); EC 3.1.3.2 (Phosphoric Monoester Hydrolases); EC 3.6.5.2 (Rab3 protein, Drosophila); EC 3.6.5.2 (rab3 GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161101
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddw352



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