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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2020.tde-24012020-122218
Document
Author
Full name
Roseane Durante Franco
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Ferro, Emer Suavinho (President)
Castro, Leandro Mantovani de
Dale, Camila Squarzoni
Rioli, Vanessa
Title in Portuguese
Caracterização fenotípica de camundongos knockout para as oligopeptidases thimet oligopeptidase e neurolisina.
Keywords in Portuguese
Aprendizado
Expressão gênica
Memória
Thimet oligopeptidases
Abstract in Portuguese
A ação concomitante do proteassomo e de peptidases intracelulares, como a thimet oligopeptidase (THOP1) e a neurolisina (Nln), podem levar à formação contínua de peptídeos funcionais. O proteassomo controla a disponibilidade de proteínas importantes para a plasticidade sináptica, sendo fundamental para aquisição e manutenção da memória. O objetivo deste trabalho foi avaliar a participação das oligopeptidases THOP1 e Nln em processos de memória e aprendizado. Como modelo experimental foram utilizados camundongos C57BL6 selvagens (WT) ou com supressão genética (knockout, KO) da THOP1 (THOP1-/-), Nln (Nln-/-) ou THOP1/Nln (THOP1/Nln-/-). Os resultados obtidos até o momento sugerem que esses animais possuem alterações cognitivas, além de comportamentos semelhantes à depressão e a esquizofrenia. A análise global da expressão gênica no córtex pré-frontal, estriado, hipocampo e hipotálamo desses animais sugere alterações que não puderam ser diretamente relacionadas aos fenótipos observados. Por outro lado, o mRNA dos receptores de dopamina aparece reduzido no córtex pré-frontal e no hipocampo, e aumentado no estriado dos animais THOP1-/- em comparação aos camundongos WT. As análises peptidômicas sugerem a alteração nos níveis relativos de peptídeos como o SANSNPAMAPRE, que tem como precursor o neuropeptídeo somatostatina, e RKGPGPGGPGGAGGARGGAGGGPSGD, cuja proteína precursora é a neurogranina. A taxa de turnover de serotonina e dopamina no córtex pré-frontal dos animais THOP1-/- encontrou-se alterada, o que poderia explicar uma possível correlação funcional com os fenótipos observados. Em conjunto, esses resultados sugerem a participação das oligopeptidases THOP1 e Nln na consolidação da memória e aprendizado, bem como em distúrbios psiquiátricos. Os mecanismos moleculares ainda demandam investigações adicionais, mas sugerem o envolvimento de peptídeos secretados, derivados da somatostatina, e intracelulares, derivados da neurogranina.
Title in English
Phenotypic characterization of thimet oligopeptidase and neurolysin knockout mice.
Keywords in English
Gene expression
Learning
Memory
Thimet oligopeptidases
Abstract in English
The concomitant action of proteasome and intracellular peptidases, such as thimet oligopeptidase (THOP1) and neurolysin (Nln), may lead to the continuous formation of functional peptides. Proteasome controls the availability of proteins and is important for synaptic plasticity, which has been suggested to be essential for memory acquisition and maintenance. Here, our main aim is to evaluate the participation of oligopeptidases THOP1 and Nln in memory and learning processes. Wild type (WT) C57BL6 or genetically modified (knockout) THOP1 (THOP1-/-), Nln (Nln-/-) or THOP1/Nln (THOP1/Nln-/-) mice were used as experimental models. The results obtained suggest that these animals have cognitive alterations, besides behaviors similar to depression and schizophrenic disorder. The global analysis of gene expression in the prefrontal cortex, striatum, hippocampus and hypothalamus of these animals, suggests alterations that could not be directly related to the observed phenotypes. On the other hand, dopamine receptor mRNA appears reduced in the prefrontal cortex and hippocampus, and increased in the striatum of THOP1-/- mice compared to WT mice. Peptidomic analyzes suggest alterations in the relative level of specific peptides, including SANSNPAMAPRE, derived from somatostatin, and RKGPGPGGPGGAGGARGGAGGGPSGD, derived from neurogranin. The turnover rate of serotonin and dopamine in the prefrontal cortex of THOP1-/- was altered, which could explain a possible functional correlation with the observed phenotypes. Taken together, these results suggest the involvement of oligopeptidases THOP1 and Nln in memory and learning consolidation, as well as in psychiatric disorders. The molecular mechanisms still require further investigations, suggesting the involvement of secreted peptides, such the ones derived form as somatostatin, and intracellular peptides, such the ones derivative from neurogranin.
 
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Release Date
2022-01-23
Publishing Date
2020-01-28
 
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