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1.
J Biol Chem ; 276(48): 45394-402, 2001 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-11574530

RESUMO

Intramembranous cleavage of the beta-amyloid precursor protein by gamma-secretase is the final processing event generating amyloid-beta peptides, which are thought to be causative agents for Alzheimer's disease. Missense mutations in the presenilin genes co-segregate with early-onset Alzheimer's disease, and, recently, a close biochemical linkage between presenilins and the identity of gamma-secretase has been established. Here we describe for the first time that certain potent gamma-secretase inhibitors are able to interfere with the endoproteolytic processing of presenilin 1 (PS1). In addition, we identified a novel gamma-secretase inhibitor, [1S-benzyl-4R-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-ylcarbamoyl)-S-ethylcarbamoyl]-2R-hydroxy-5-phenyl-pentyl]-carbamic acid tert-butyl ester (CBAP), which not only physically interacts with PS1, but upon chronic treatment produces a "pharmacological knock-down" of PS1 fragments. This indicates that the observed accumulation of full-length PS1 is caused by a direct inhibition of its endoproteolysis. The subsequent use of CBAP as a biological tool to increase full-length PS1 levels in the absence of exogenous PS1 expression has provided evidence that wild-type PS1 endoproteolysis is not required either for PS1/gamma-secretase complex assembly or trafficking. Furthermore, in cell-based systems CBAP does not completely recapitulate PS1 loss-of-function phenotypes. Even though the beta-amyloid precursor protein cleavage and the S3 cleavage of the Notch receptor are inhibited by CBAP, an impairment of Trk receptor maturation was not observed.


Assuntos
Endopeptidases/química , Inibidores Enzimáticos/farmacologia , Proteínas de Membrana/química , Proteínas de Membrana/genética , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Membrana Celular/metabolismo , Células Cultivadas , Centrifugação , DNA Complementar/metabolismo , Dimerização , Relação Dose-Resposta a Droga , Endopeptidases/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Proteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Fenótipo , Presenilina-1 , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Frações Subcelulares , Fatores de Tempo , Transfecção , Células Tumorais Cultivadas , Raios Ultravioleta
2.
J Biol Chem ; 275(18): 13191-4, 2000 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-10747861

RESUMO

Peripherin/rds is an integral membrane glycoprotein found in the rim regions of vertebrate photoreceptor cell discs. Natural mutations of the encoding gene result in degenerative retinal disorders, such as retinitis pigmentosa. The retinal degeneration slow (rds) phenotype, observed in mice, is considered to be an appropriate model for peripherin/rds-mediated retinitis pigmentosa. Associated abnormalities in the outer segment of photoreceptor cells have implicated peripherin/rds in some aspect of disc morphology, yet it remains unclear whether such morphological effects are the cause or the result of this condition. Here we present the first direct evidence to support a role for peripherin/rds in maintaining the flattened vesicle morphology characteristic of photoreceptor outer segments. In vitro expression yields a 36-kDa immunoreactive species, which is inserted into membranes and undergoes N-glycosylation, inter- and intramolecular disulfide bonding, and dimerization. Electron microscopy reveals that peripherin/rds flattens microsomal vesicles. This effect appears to be dependent on disulfide bond formation but not N-glycosylation. The inability of two pathogenic peripherin/rds mutants (P216L and C165Y) to flatten membrane vesicles implicates such mutations as the primary cause of the retinal degeneration observed in retinitis pigmentosa.


Assuntos
Grânulos Citoplasmáticos/fisiologia , Proteínas de Filamentos Intermediários/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Retina/fisiologia , Retina/ultraestrutura , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/ultraestrutura , Animais , Membrana Celular/fisiologia , Membrana Celular/ultraestrutura , Células Cultivadas , Grânulos Citoplasmáticos/ultraestrutura , Proteínas do Olho/fisiologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Periferinas , Degeneração Retiniana/patologia , Degeneração Retiniana/fisiopatologia
3.
Appl Opt ; 6(3): 586-7, 1967 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20057809
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