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1.
Mol Psychiatry ; 19(10): 1143-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23999527

RESUMO

In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.


Assuntos
Autoanticorpos/sangue , Barreira Hematoencefálica/metabolismo , Transtornos do Humor/metabolismo , Doença de Parkinson/metabolismo , Receptores de N-Metil-D-Aspartato/imunologia , Esquizofrenia/metabolismo , Adulto , Idoso , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Córtex Cerebral/metabolismo , Endocitose/fisiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Influenza Humana/genética , Influenza Humana/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Transtornos do Humor/genética , Neurônios/metabolismo , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética
2.
J Biol Chem ; 274(39): 27651-7, 1999 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-10488105

RESUMO

Integrin alpha(7)-deficient mice develop a novel form of muscular dystrophy. Here we report that deficiency of alpha(7) integrin causes an activation of the c-Raf-1/mitogen-activated protein (MAP) 2 kinase signal transduction pathway in muscle cells. The observed activation of c-Raf-1/MAP2 kinases is a specific effect, because the alpha(7) integrin deficiency does not cause unspecific stress as determined by measurement of the Hsp72/73 level and activity of the JNK2 kinase. Because an increased level of activated FAK was found in muscle of alpha(7) integrin-deficient mice, the activation of c-Raf-1 kinase is triggered most likely by an integrin-dependent pathway. In accordance with this, in the integrin alpha(7)-deficient mice, part of the integrin beta(1D) variant in muscle is replaced by the beta(1A) variant, which permits the FAK activation. A recent report describes that integrin activity can be down-modulated by the c-Raf-1/MAP2 kinase pathway. Specific activation of the c-Raf-1/MAP2 kinases by cell-permeable peptides in skeletal muscle of rabbits causes degeneration of muscle fibers. Therefore, we conclude that in alpha(7) integrin-deficient mice, the continuous activation of c-Raf-1 kinase causes a permanent reduction of integrin activity diminishing integrin-dependent cell-matrix interactions and thereby contributing to the development of the dystrophic phenotype.


Assuntos
Antígenos CD/fisiologia , Proteínas de Choque Térmico HSP70 , Cadeias alfa de Integrinas , Fígado/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno , Músculo Esquelético/metabolismo , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais/fisiologia , Animais , Antígenos CD/genética , Proteínas de Transporte/metabolismo , Diafragma , Ativação Enzimática , Proteínas de Choque Térmico HSC70 , Proteínas de Choque Térmico HSP72 , Proteínas de Choque Térmico/metabolismo , Membro Posterior , Camundongos , Camundongos Knockout , Proteína Quinase 9 Ativada por Mitógeno , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citologia , Coelhos
3.
J Neurol Sci ; 163(2): 140-52, 1999 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-10371075

RESUMO

The integrins are a large family of heterodimeric transmembrane cellular receptors which mediate the association between the extracellular matrix (ECM) and cytoskeletal proteins. The alpha7beta1 integrin is a major laminin binding integrin in skeletal and cardiac muscle and is thought to be involved in myogenic differentiation and migration processes. The main binding partners of the alpha7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1). Targeted deletion of the gene for the alpha7 integrin subunit (ITGA7) in mice leads to a novel form of muscular dystrophy. In the present study we have investigated the expression of two alternative splice variants, the alpha7B and beta1D integrin subunits, in normal human skeletal muscle, as well as in various forms of muscular dystrophy. In normal human skeletal muscle the expression of the alpha7 integrin subunit appeared to be developmentally regulated: it was first detected at 2 years of age. In contrast, the beta1D integrin could be detected in immature and mature muscle in the sarcolemma of normal fetal skeletal muscle at 18 weeks gestation. The expression of alpha7B integrin was significantly reduced at the sarcolemma in six patients with laminin alpha2 chain deficient congenital muscular dystrophy (CMD) (age >2 years). However, this reduction was not correlated with the amount of laminin alpha2 chain expressed. In contrast, the expression of the laminin alpha2 chain was not altered in the skeletal muscle of the alpha7 knock-out mice. These data argue in favor that there is not a tight correlation between the expression of the alpha7 integrin subunit and that of the laminin alpha2 chain in either human or murine dystrophic muscle. Interestingly, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of alpha7B was upregulated irrespective of the level of dystrophin expression as shown by a strong sarcolemmal staining pattern even in young boys (age <2 years). The expression of the beta1D integrin subunit was not altered in any of our patients with different types of muscular dystrophy. In contrast, sarcolemmal expression of beta1D integrin was significantly reduced in the alpha7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of alpha7B in laminin alpha2 chain deficiency defines a biochemical change in the composition of the plasma membrane resulting from a primary protein deficiency in the basal lamina. These findings, in addition to the occurrence of a muscular dystrophy in alpha7 deficient mice, implies that the alpha7B integrin is an important laminin receptor within the plasma membrane which plays a significant role in skeletal muscle function and stability.


Assuntos
Antígenos CD/genética , Cadeias alfa de Integrinas , Laminina/deficiência , Laminina/genética , Músculo Esquelético/fisiopatologia , Distrofias Musculares/genética , Adolescente , Adulto , Envelhecimento , Sequência de Aminoácidos , Animais , Anticorpos , Antígenos CD/fisiologia , Criança , Pré-Escolar , Proteínas do Citoesqueleto/genética , Distroglicanas , Distrofina/genética , Desenvolvimento Embrionário e Fetal , Feto , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lactente , Recém-Nascido , Integrinas/genética , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Desenvolvimento Muscular , Músculo Esquelético/embriologia , Músculo Esquelético/crescimento & desenvolvimento , Distrofias Musculares/congênito , Isoformas de Proteínas/genética , Sarcoglicanas
4.
Nat Genet ; 17(3): 318-23, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9354797

RESUMO

Integrin alpha 7 beta 1 is a specific cellular receptor for the basement membrane protein laminin-1 (refs 1,2), as well as for the laminin isoforms -2 and -4 (ref. 3). The alpha 7 subunit is expressed mainly in skeletal and cardiac muscle and has been suggested to be involved in differentiation and migration processes during myogenesis. Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle. In adult muscle, the alpha 7A and alpha 7B subunits are concentrated in myotendinous junctions but can also be detected in neuromuscular junctions and along the sarcolemmal membrane. To study the potential involvement of alpha 7 integrin, during myogenesis and its role in muscle integrity and function, we generated a null allele of the alpha 7 gene (Itga7) in the germline of mice by homologous recombination in embryonic stem (ES) cells. Surprisingly, mice homozygous for the mutation are viable and fertile, indicating that the alpha 7 beta 1 integrin is not essential for myogenesis. However, histological analysis of skeletal muscle revealed typical symptoms of a progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The observed histopathological changes strongly indicate an impairment of function of the myotendinous junctions. These findings demonstrate that alpha 7 beta 1 integrin represents an indispensable linkage between the muscle fibre and the extracellular matrix that is independent of the dystrophin-dystroglycan complex-mediated interaction of the cytoskeleton with the muscle basement membrane.


Assuntos
Antígenos CD/genética , Cadeias alfa de Integrinas , Distrofia Muscular Animal/genética , Animais , Antígenos CD/metabolismo , Extremidades/patologia , Feminino , Citometria de Fluxo/métodos , Homozigoto , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Dados de Sequência Molecular , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Fagocitose , Recombinação Genética , Tenascina/metabolismo , Tendões/patologia
5.
Virology ; 225(1): 235-9, 1996 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-8918553

RESUMO

It has been shown that a C-terminally truncated form of the middle-sized hepatitis B virus (HBV) surface protein (MHBst) functions as a transcriptional activator. This function is dependent on the cytosolic orientation of the N-terminal PreS2 domain of MHBst, but in the case of wild-type MHBs, the PreS2 domain is contranslationally translocated into the ER lumen. Recent reports demonstrated that the PreS2 domain of the large HBV surface protein (LHBs) initially remains on the cytosolic side of the ER membrane after translation. Therefore, the question arose as to whether the LHBs protein exhibits the same transcriptional activator function as MHBst. We show that LHBs, like MHBst, is indeed able to activate a variety of promoter elements. There is evidence for a PKC-dependent activation of AP-1 and NF-kappa B by LHBs. Downstream of the PKC the functionality of c-Raf-1 kinase is a prerequisite for LHBs-dependent activation of AP-1 and NF-kappa B since inhibition of c-Raf-1 kinase abolishes LHBs-dependent transcriptional activation of AP-1 and NF-kappa B.


Assuntos
Vírus da Hepatite B/genética , Transativadores/fisiologia , Proteínas do Envelope Viral/fisiologia , Carcinoma Hepatocelular , Antígenos de Superfície da Hepatite B/genética , Humanos , NF-kappa B/genética , Regiões Promotoras Genéticas/genética , Proteína Quinase C/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-raf , Proteínas Recombinantes de Fusão , Transdução de Sinais/fisiologia , Transativadores/genética , Fator de Transcrição AP-1/genética , Células Tumorais Cultivadas , Proteínas do Envelope Viral/genética
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