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[PMID]:28597296
[Au] Autor:Olsen JG; Teilum K; Kragelund BB
[Ad] Endereço:Structural Biology and NMR Laboratory (SBiNLab) and the Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
[Ti] Título:Behaviour of intrinsically disordered proteins in protein-protein complexes with an emphasis on fuzziness.
[So] Source:Cell Mol Life Sci;74(17):3175-3183, 2017 Sep.
[Is] ISSN:1420-9071
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Intrinsically disordered proteins (IDPs) do not, by themselves, fold into a compact globular structure. They are extremely dynamic and flexible, and are typically involved in signalling and transduction of information through binding to other macromolecules. The reason for their existence may lie in their malleability, which enables them to bind several different partners with high specificity. In addition, their interactions with other macromolecules can be regulated by a variable amount of chemically diverse post-translational modifications. Four kinetically and energetically different types of complexes between an IDP and another macromolecule are reviewed: (1) simple two-state binding involving a single binding site, (2) avidity, (3) allovalency and (4) fuzzy binding; the last three involving more than one site. Finally, a qualitative definition of fuzzy binding is suggested, examples are provided, and its distinction to allovalency and avidity is highlighted and discussed.
[Mh] Termos MeSH primário: Proteínas Intrinsicamente Desordenadas/metabolismo
[Mh] Termos MeSH secundário: Animais
Clatrina/química
Clatrina/metabolismo
Seres Humanos
Proteínas Intrinsicamente Desordenadas/química
Cinética
Modelos Moleculares
Proteínas Monoméricas de Montagem de Clatrina/química
Proteínas Monoméricas de Montagem de Clatrina/metabolismo
Complexo de Proteínas Formadoras de Poros Nucleares/química
Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
Proteínas de Transporte Nucleocitoplasmático/química
Proteínas de Transporte Nucleocitoplasmático/metabolismo
Ligação Proteica
Processamento de Proteína Pós-Traducional
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Clathrin); 0 (Intrinsically Disordered Proteins); 0 (Monomeric Clathrin Assembly Proteins); 0 (Nuclear Pore Complex Proteins); 0 (Nucleocytoplasmic Transport Proteins); 0 (clathrin assembly protein AP180)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170610
[St] Status:MEDLINE
[do] DOI:10.1007/s00018-017-2560-7


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[PMID]:28316001
[Au] Autor:Vacínová G; Vejrazková D; Lukásová P; Lischková O; Dvoráková K; Rusina R; Holmerová I; Vanková H; Vcelák J; Bendlová B; Vanková M
[Ad] Endereço:Department of Molecular Endocrinology, Institute of Endocrinology, Národní 8, Prague, 116 94, Czech Republic. gvacinova@endo.cz.
[Ti] Título:Associations of polymorphisms in the candidate genes for Alzheimer's disease BIN1, CLU, CR1 and PICALM with gestational diabetes and impaired glucose tolerance.
[So] Source:Mol Biol Rep;44(2):227-231, 2017 Apr.
[Is] ISSN:1573-4978
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Alzheimer's disease (AD) is the most common type of dementia, with a prevalence that is rising every year. AD is associated with type 2 diabetes mellitus (T2DM) and insulin resistance, and is therefore sometimes called "type 3 diabetes mellitus". The aim of this study was to examine whether the variants of some candidate genes involved in the development of AD, namely BIN1 (rs744373), CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179), are related to several disorders of glucose metabolism-gestational diabetes (GDM), T2DM and impaired glucose tolerance (IGT). Our study included 550 women with former GDM and 717 control women, 392 patients with T2DM and 180 non-diabetic controls, and 117 patients with IGT and 630 controls with normal glucose tolerance. Genotyping analysis was performed using specially-designed TaqMan assays. No significant associations of the genetic variants rs744373 in BIN1, rs11136000 in CLU, or rs3818361 in CR1 were found with GDM, T2DM or IGT, but rs3851179 in PICALM was associated with an increased risk of GDM. The frequency of the AD risk-associated C allele was significantly higher in the GDM group compared to controls: OR 1.21; 95% CI (1.03-1.44). This finding was not apparent in T2DM and IGT; conversely, the C allele of the PICALM SNP was protective for IGT: OR 0.67; 95% CI (0.51-0.89). This study demonstrates an association between PICALM rs3851179 and GDM as well as IGT. However, elucidation of the possible role of this gene in the pathogenesis of GDM requires further independent studies.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Diabetes Gestacional/genética
Intolerância à Glucose/genética
Proteínas Monoméricas de Montagem de Clatrina/genética
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/sangue
Proteínas Adaptadoras de Transdução de Sinal/genética
Adulto
Idoso
Alelos
Doença de Alzheimer/complicações
Clusterina/sangue
Clusterina/genética
Diabetes Mellitus Tipo 2/genética
Diabetes Gestacional/metabolismo
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Frequência do Gene
Estudos de Associação Genética/métodos
Predisposição Genética para Doença
Variação Genética
Intolerância à Glucose/metabolismo
Seres Humanos
Meia-Idade
Proteínas Monoméricas de Montagem de Clatrina/sangue
Proteínas Nucleares/sangue
Proteínas Nucleares/genética
Razão de Chances
Polimorfismo de Nucleotídeo Único/genética
Gravidez
Receptores de Complemento 3b/sangue
Receptores de Complemento 3b/genética
Fatores de Risco
Proteínas Supressoras de Tumor/sangue
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (BIN1 protein, human); 0 (CLU protein, human); 0 (CR1 protein, human); 0 (Clusterin); 0 (Monomeric Clathrin Assembly Proteins); 0 (Nuclear Proteins); 0 (PICALM protein, human); 0 (Receptors, Complement 3b); 0 (Tumor Suppressor Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170320
[St] Status:MEDLINE
[do] DOI:10.1007/s11033-017-4100-9


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[PMID]:28242260
[Au] Autor:Kumar A; Dumasia K; Deshpande S; Balasinor NH
[Ad] Endereço:Department of Neuroendocrinology, National Institute for Research in Reproductive Health (ICMR), Parel, Mumbai 400012, India.
[Ti] Título:Direct regulation of genes involved in sperm release by estrogen and androgen through their receptors and coregulators.
[So] Source:J Steroid Biochem Mol Biol;171:66-74, 2017 Jul.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Steroid hormones, estrogen and androgen, control transcription in various reproductive and non-reproductive tissues. Both hormones are known to be important for control of sperm release from the seminiferous epithelium (spermiation), a process characterized by extensive remodeling of actin filaments and endocytosis. Earlier studies with an estrogen (E2)-induced rat model of spermiation failure revealed genes involved in actin remodeling (Arpc1b and Evl) and endocytosis (Picalm, Eea1, and Stx5a) to be differentially regulated. Further, among these genes, Arpc1b and Evl were found to be estrogen-responsive whereas Eea1 and Stx5a were androgen-responsive and Picalm was responsive to both hormones in seminiferous tubule cultures. Yet, the mechanism by which these genes are regulated by estrogen and androgen in the testis was unclear. Here, we report the presence of a functional estrogen response element (ERE) upstream of Arpc1b and Evl genes and androgen response element (ARE) upstream of Picalm, Eea1, and Stx5a genes. Chromatin immunoprecipitation in control versus E2-treated testes revealed significant changes in estrogen receptor beta (ERß) recruitment along with coregulators to the EREs upstream of Arpc1b and Evl genes and androgen receptor (AR) at AREs upstream of Picalm, Eea1, and Stx5a genes. Enrichment patterns of these EREs/AREs with coregulators, activating and repressing histone modifications along with RNA polymerase II recruitment, correlated with the observed expression patterns of these genes upon E2 treatment. Taken together, our results reveal direct targets of estrogen and androgen in the testes and provide insights into transcriptional control of sperm release by the two steroid hormones.
[Mh] Termos MeSH primário: Complexo 2-3 de Proteínas Relacionadas à Actina/agonistas
Receptor beta de Estrogênio/agonistas
Estrogênios/farmacologia
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos
Proteínas dos Microfilamentos/agonistas
Fosfoproteínas/agonistas
Elementos de Resposta/efeitos dos fármacos
Espermatozoides/efeitos dos fármacos
[Mh] Termos MeSH secundário: Complexo 2-3 de Proteínas Relacionadas à Actina/genética
Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo
Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Androgênios/metabolismo
Animais
Células Cultivadas
Imunoprecipitação da Cromatina
Estradiol/administração & dosagem
Receptor beta de Estrogênio/metabolismo
Estrogênios/administração & dosagem
Injeções Subcutâneas
Masculino
Proteínas dos Microfilamentos/genética
Proteínas dos Microfilamentos/metabolismo
Proteínas Monoméricas de Montagem de Clatrina/agonistas
Proteínas Monoméricas de Montagem de Clatrina/genética
Proteínas Monoméricas de Montagem de Clatrina/metabolismo
Fosfoproteínas/genética
Fosfoproteínas/metabolismo
Proteínas Qa-SNARE/agonistas
Proteínas Qa-SNARE/genética
Proteínas Qa-SNARE/metabolismo
Ratos Sprague-Dawley
Receptores Androgênicos/química
Receptores Androgênicos/metabolismo
Células de Sertoli/citologia
Células de Sertoli/efeitos dos fármacos
Células de Sertoli/metabolismo
Espermatogênese/efeitos dos fármacos
Espermatozoides/citologia
Espermatozoides/metabolismo
Proteínas de Transporte Vesicular/agonistas
Proteínas de Transporte Vesicular/genética
Proteínas de Transporte Vesicular/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actin-Related Protein 2-3 Complex); 0 (Androgens); 0 (Arpc1b protein, rat); 0 (EVL protein, rat); 0 (Estrogen Receptor beta); 0 (Estrogens); 0 (Microfilament Proteins); 0 (Monomeric Clathrin Assembly Proteins); 0 (Phosphoproteins); 0 (Picalm protein, rat); 0 (Qa-SNARE Proteins); 0 (Receptors, Androgen); 0 (Vesicular Transport Proteins); 0 (early endosome antigen 1); 4TI98Z838E (Estradiol)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE


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[PMID]:28073596
[Au] Autor:Ponomareva NV; Andreeva TV; Protasova MS; Shagam LI; Malina DD; Goltsov AY; Fokin VF; Illarioshkin SN; Rogaev EI
[Ad] Endereço:Research Center of Neurology, Moscow, Russia; Vavilov Institute of General Genetics, RAS, Moscow, Russia. Electronic address: ponomare@yandex.ru.
[Ti] Título:Quantitative EEG during normal aging: association with the Alzheimer's disease genetic risk variant in PICALM gene.
[So] Source:Neurobiol Aging;51:177.e1-177.e8, 2017 Mar.
[Is] ISSN:1558-1497
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Genome-wide association studies have identified novel risk variants for Alzheimer's disease (AD). Among these, a gene carrying one of the highest risks for AD is PICALM. The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain function in nondemented subjects remains largely unknown. We examined the possible effect of the PICALM rs3851179 genotype on quantitative electroencephalography recording at rest in 137 nondemented volunteers (age range: 20-79 years) subdivided into cohorts of those younger than and those older than 50 years of age. The homozygous presence of the AD risk variant PICALM GG was associated with an increase in beta relative power, with the effect being more pronounced in the older cohort. Beta power elevation in resting-state electroencephalography has previously been linked to cortical disinhibition and hyperexcitability. The increase in beta relative power in the carriers of the AD risk PICALM GG genotype suggests changes in the cortical excitatory-inhibitory balance, which are heightened during normal aging.
[Mh] Termos MeSH primário: Envelhecimento/fisiologia
Doença de Alzheimer/genética
Doença de Alzheimer/fisiopatologia
Eletroencefalografia
Estudo de Associação Genômica Ampla
Genótipo
Proteínas Monoméricas de Montagem de Clatrina/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Estudos de Coortes
Feminino
Seres Humanos
Masculino
Meia-Idade
Risco
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Monomeric Clathrin Assembly Proteins); 0 (PICALM protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170112
[St] Status:MEDLINE


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[PMID]:27574975
[Au] Autor:Moshkanbaryans L; Xue J; Wark JR; Robinson PJ; Graham ME
[Ad] Endereço:Synapse Proteomics Group, Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia.
[Ti] Título:A Novel Sequence in AP180 and CALM Promotes Efficient Clathrin Binding and Assembly.
[So] Source:PLoS One;11(8):e0162050, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The clathrin heavy chain N-terminal domain interacts with endocytic adapter proteins via clathrin binding motifs to assemble clathrin triskelia into cages. However, the precise mechanism of clathrin assembly is not yet known. Clathrin assembly protein AP180 has more clathrin binding motifs than any other endocytic protein and has a major role in the assembly of the clathrin coat during synaptic vesicle biogenesis. We now demonstrate that some of the previously identified binding motifs in AP180 may be non-functional and that a non-conventional clathrin binding sequence has a major influence on AP180 function. The related protein, clathrin assembly lymphoid myeloid leukemia protein (CALM), has fewer clathrin binding motifs and functions ubiquitously in clathrin-mediated endocytosis. The C-terminal ~16 kDa sub-domain in AP180, which has relatively high similarity with CALM, was shown in earlier work to have an unexplained role in clathrin binding. We identified the specific sequences in this sub-domain that bind to clathrin. Evidence for a role for these sequences in promoting clathrin binding was examined using in vitro and ex vivo experiments that compared the clathrin binding ability of site mutants with the wild type sequence. A sequence conserved in both AP180 and CALM (LDSSLA[S/N]LVGNLGI) was found to be the major interaction site and mutation caused a deficit in clathrin assembly, which is the first example of a mutation having this effect. In contrast, single or double mutation of DL(L/F) motifs in full length AP180 had no significant effect on clathrin binding, despite higher clathrin affinity for isolated peptides containing these motifs. We conclude that the novel clathrin interaction sites identified here in CALM and AP180 have a major role in how these proteins interface with clathrin. This work advances the case that AP180 and CALM are required to use a combination of standard clathrin N-terminal domain binding motifs and the sequence identified here for optimal binding and assembling clathrin.
[Mh] Termos MeSH primário: Clatrina/metabolismo
Endocitose
Proteínas Monoméricas de Montagem de Clatrina/química
Proteínas Monoméricas de Montagem de Clatrina/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sítios de Ligação
Sequência Conservada
Seres Humanos
Camundongos
Proteínas Monoméricas de Montagem de Clatrina/metabolismo
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Clathrin); 0 (Monomeric Clathrin Assembly Proteins); 0 (PICALM protein, human); 0 (PICALM protein, mouse); 0 (clathrin assembly protein AP180)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160831
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0162050


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[PMID]:27482534
[Au] Autor:Harrison TM; Mahmood Z; Lau EP; Karacozoff AM; Burggren AC; Small GW; Bookheimer SY
[Ad] Endereço:Neuroscience Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, California 90095; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California 90095.
[Ti] Título:An Alzheimer's Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults.
[So] Source:eNeuro;3(3), 2016 May-Jun.
[Is] ISSN:2373-2822
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Variants at 21 genetic loci have been associated with an increased risk for Alzheimer's disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = -0.40; p = 0.003; WRS: r = -0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = -0.35; p = 0.009; WRS: r = -0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.
[Mh] Termos MeSH primário: Envelhecimento/genética
Envelhecimento/patologia
Doença de Alzheimer/diagnóstico por imagem
Doença de Alzheimer/genética
Predisposição Genética para Doença
Hipocampo/diagnóstico por imagem
[Mh] Termos MeSH secundário: Envelhecimento/psicologia
Doença de Alzheimer/psicologia
Apolipoproteínas E/genética
Ensaios Clínicos como Assunto
Clusterina/genética
Grupo com Ancestrais do Continente Europeu
Feminino
Seguimentos
Hipocampo/patologia
Seres Humanos
Estudos Longitudinais
Imagem por Ressonância Magnética
Masculino
Entrevista Psiquiátrica Padronizada
Meia-Idade
Proteínas Monoméricas de Montagem de Clatrina/genética
Herança Multifatorial
Análise Multivariada
Testes Neuropsicológicos
Tamanho do Órgão
Sintomas Prodrômicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (CLU protein, human); 0 (Clusterin); 0 (Monomeric Clathrin Assembly Proteins); 0 (PICALM protein, human)
[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:160803
[St] Status:MEDLINE


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[PMID]:27466196
[Au] Autor:Kanatsu K; Hori Y; Takatori S; Watanabe T; Iwatsubo T; Tomita T
[Ad] Endereço:Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
[Ti] Título:Partial loss of CALM function reduces Aß42 production and amyloid deposition in vivo.
[So] Source:Hum Mol Genet;25(18):3988-3997, 2016 Sep 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aberrant production, clearance and deposition of amyloid-ß protein (Aß) in the human brain have been implicated in the aetiology of Alzheimer disease (AD). γ-Secretase is the enzyme responsible for generating various Aß species, such as Aß40 and toxic Aß42. Recently, genome-wide association studies in late-onset AD patients have identified the endocytosis-related phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a genetic risk factor for AD. We previously found that the loss of expression of CALM protein encoded by PICALM affects the ratio of production of Aß42, through the regulation of the clathrin-mediated endocytosis of γ-secretase. Here, we show that the binding capacity of the assembly protein 180 N-terminal homology (ANTH) domain of CALM to phosphatidylinositol-4,5-biphosphate, as well as to nicastrin, is critical to the modulation of the internalization of γ-secretase and to the Aß42 production ratio. Moreover, reduction of CALM decreases Aß deposition as well as brain levels of insoluble Aß42 in vivo These results suggest that CALM expression modifies AD risk by regulating Aß pathology.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Secretases da Proteína Precursora do Amiloide/genética
Peptídeos beta-Amiloides/genética
Proteínas Monoméricas de Montagem de Clatrina/genética
Fragmentos de Peptídeos/genética
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Amiloide/metabolismo
Secretases da Proteína Precursora do Amiloide/metabolismo
Encéfalo/metabolismo
Encéfalo/patologia
Endocitose/genética
Seres Humanos
Cinética
Glicoproteínas de Membrana/genética
Glicoproteínas de Membrana/metabolismo
Proteínas Monoméricas de Montagem de Clatrina/biossíntese
Mutação
Fosfatidilinositol 4,5-Difosfato/metabolismo
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid); 0 (Amyloid beta-Peptides); 0 (Membrane Glycoproteins); 0 (Monomeric Clathrin Assembly Proteins); 0 (PICALM protein, human); 0 (Peptide Fragments); 0 (Phosphatidylinositol 4,5-Diphosphate); 0 (amyloid beta-protein (1-42)); 0 (nicastrin protein); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170720
[Lr] Data última revisão:
170720
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160729
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddw239


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[PMID]:27430330
[Au] Autor:Thomas RS; Henson A; Gerrish A; Jones L; Williams J; Kidd EJ
[Ad] Endereço:School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
[Ti] Título:Decreasing the expression of PICALM reduces endocytosis and the activity of ß-secretase: implications for Alzheimer's disease.
[So] Source:BMC Neurosci;17(1):50, 2016 Jul 18.
[Is] ISSN:1471-2202
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Polymorphisms in the gene for phosphatidylinositol binding clathrin assembly protein (PICALM), an endocytic-related protein, are associated with a small, increased risk of developing Alzheimer's disease (AD), strongly suggesting that changes in endocytosis are involved in the aetiology of the disease. We have investigated the involvement of PICALM in the processing of amyloid precursor protein (APP) to understand how PICALM could be linked to the development of AD. We used siRNA to deplete levels of PICALM, its isoforms and clathrin heavy chain in the human brain-derived H4 neuroglioma cell line that expresses endogenous levels of APP. We then used Western blotting, ELISA and immunohistochemistry to detect intra- and extracellular protein levels of endocytic-related proteins, APP and APP metabolites including ß-amyloid (Aß). Levels of functional endocytosis were quantified using ALEXA 488-conjugated transferrin and flow cytometry as a marker of clathrin-mediated endocytosis (CME). RESULTS: Following depletion of all the isoforms of PICALM by siRNA in H4 cells, levels of intracellular APP, intracellular ß-C-terminal fragment (ß-CTF) and secreted sAPPß (APP fragments produced by ß-secretase cleavage) were significantly reduced but Aß40 was not affected. Functional endocytosis was significantly reduced after both PICALM and clathrin depletion, highlighting the importance of PICALM in this process. However, depletion of clathrin did not affect APP but did reduce ß-CTF levels. PICALM depletion altered the intracellular distribution of clathrin while clathrin reduction affected the subcellular pattern of PICALM labelling. Both PICALM and clathrin depletion reduced the expression of BACE1 mRNA and PICALM siRNA reduced protein levels. Individual depletion of PICALM isoforms 1 and 2 did not affect APP levels while clathrin depletion had a differential effect on the isoforms, increasing isoform 1 while decreasing isoform 2 expression. CONCLUSIONS: The depletion of PICALM in brain-derived cells has significant effects on the processing of APP, probably by reducing CME. In particular, it affects the production of ß-CTF which is increasingly considered to be an important mediator in AD independent of Aß. Thus a decrease in PICALM expression in the brain could be beneficial to slow or prevent the development of AD.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/metabolismo
Endocitose/fisiologia
Proteínas Monoméricas de Montagem de Clatrina/deficiência
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Peptídeos beta-Amiloides/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Western Blotting
Encéfalo/metabolismo
Linhagem Celular Tumoral
Cadeias Pesadas de Clatrina/genética
Cadeias Pesadas de Clatrina/metabolismo
Ensaio de Imunoadsorção Enzimática
Citometria de Fluxo
Seres Humanos
Imuno-Histoquímica
Proteínas Monoméricas de Montagem de Clatrina/genética
Fragmentos de Peptídeos/metabolismo
Isoformas de Proteínas/deficiência
Isoformas de Proteínas/genética
RNA Mensageiro/metabolismo
RNA Interferente Pequeno
Transferrina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APP protein, human); 0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Monomeric Clathrin Assembly Proteins); 0 (PICALM protein, human); 0 (Peptide Fragments); 0 (Protein Isoforms); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Transferrin); 0 (amyloid beta-protein (1-40)); 114899-12-6 (Clathrin Heavy Chains); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160720
[St] Status:MEDLINE
[do] DOI:10.1186/s12868-016-0288-1


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[PMID]:26945057
[Au] Autor:Clifford RJ; Maryon EB; Kaplan JH
[Ad] Endereço:Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, IL 60607, USA.
[Ti] Título:Dynamic internalization and recycling of a metal ion transporter: Cu homeostasis and CTR1, the human Cu⁺ uptake system.
[So] Source:J Cell Sci;129(8):1711-21, 2016 Apr 15.
[Is] ISSN:1477-9137
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cu ion (Cu) entry into human cells is mediated by CTR1 (also known as SLC31A1), the high-affinity Cu transporter. When extracellular Cu is raised, the cell is protected against excess accumulation by rapid internalization of the transporter. When Cu is lowered, the transporter returns to the membrane. We show in HEK293 cells overexpressing CTR1 that expression of either the C-terminal domain of AP180 (also known as SNAP91), a clathrin-coat assembly protein that sequesters clathrin, or a dominant-negative mutant of dynamin, decreases Cu-induced endocytosis of CTR1, as does a dynamin inhibitor and clathrin knockdown using siRNA. Utilizing imaging, siRNA techniques and a new high-throughput assay for endocytosis employing CLIP-tag methodology, we show that internalized CTR1 accumulates in early sorting endosomes and recycling compartments (containing Rab5 and EEA1), but not in late endosomes or lysosomal pathways. Using live cell fluorescence, we find that upon extracellular Cu removal CTR1 recycles to the cell surface through the slower-recycling Rab11-mediated pathway. These processes enable cells to dynamically alter transporter levels at the plasma membrane and acutely modulate entry as a safeguard against excess cellular Cu.
[Mh] Termos MeSH primário: Proteínas de Transporte de Cátions/metabolismo
Clatrina/metabolismo
Cobre/metabolismo
Dinaminas/metabolismo
Endossomos/metabolismo
[Mh] Termos MeSH secundário: Clatrina/genética
Dinaminas/genética
Endocitose
Células HEK293
Homeostase
Seres Humanos
Transporte de Íons
Proteínas Monoméricas de Montagem de Clatrina/genética
Proteínas Monoméricas de Montagem de Clatrina/metabolismo
Mutação/genética
Transporte Proteico
RNA Interferente Pequeno
Proteínas de Transporte Vesicular/metabolismo
Proteínas rab de Ligação ao GTP/metabolismo
Proteínas rab5 de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cation Transport Proteins); 0 (Clathrin); 0 (Monomeric Clathrin Assembly Proteins); 0 (RNA, Small Interfering); 0 (SLC31A1 protein, human); 0 (Vesicular Transport Proteins); 0 (clathrin assembly protein AP180); 0 (early endosome antigen 1); 789U1901C5 (Copper); EC 3.6.1.- (rab11 protein); EC 3.6.5.2 (rab GTP-Binding Proteins); EC 3.6.5.2 (rab5 GTP-Binding Proteins); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170415
[Lr] Data última revisão:
170415
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160306
[St] Status:MEDLINE
[do] DOI:10.1242/jcs.173351


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[PMID]:26889634
[Au] Autor:Barrett MJ; Koeppel AF; Flanigan JL; Turner SD; Worrall BB
[Ad] Endereço:Department of Neurology, University of Virginia, Charlottesville, VA, USA.
[Ti] Título:Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition.
[So] Source:J Parkinsons Dis;6(1):119-24, 2016.
[Is] ISSN:1877-718X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. OBJECTIVE: The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). METHODS: Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. RESULTS: In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE <  24) in PD subjects > 70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects ≤ 70 years old. CONCLUSIONS: Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.
[Mh] Termos MeSH primário: Doença de Alzheimer/etiologia
Doença de Alzheimer/genética
Proteínas Monoméricas de Montagem de Clatrina/genética
Doença de Parkinson/complicações
[Mh] Termos MeSH secundário: Idoso
Cognição
Feminino
Predisposição Genética para Doença/genética
Estudo de Associação Genômica Ampla
Genótipo
Seres Humanos
Masculino
Meia-Idade
Doença de Parkinson/genética
Polimorfismo de Nucleotídeo Único/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Monomeric Clathrin Assembly Proteins); 0 (PICALM protein, human)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170117
[Lr] Data última revisão:
170117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160219
[St] Status:MEDLINE
[do] DOI:10.3233/JPD-150706



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