Avaliação das alterações moleculares associadas ao prejuízo cognitivo exibido por camundongos adultos que carregam o polimorfismo genético Ala92-D2
Tipo
TCC
Data de publicação
2022-12
Periódico
Citações (Scopus)
Autores
Coviello, Beatriz Martin
Orientador
Ribeiro, Miriam Oliveira
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Resumo
O polimorfismo Ala92-D2 é uma alteração genética da enzima que catalisa a conversão de T4 a T3, a desiodase do tipo 2, e está presente em uma porção significativa da população mundial (12 a 36%). A Ala92-D2 exibe baixa atividade catalítica, está associada ao estresse do Retículo Endoplasmático (RE) e a prejuízos na cognição. Resultados prévios obtidos em nosso laboratório mostram que os prejuízos de memória dos camundongos Ala92-D2 pioram significativamente aos sete meses de idade. A performance dos animais no teste de reconhecimento social é boa aos 2 meses, com os animais Ala92-D2 sendo capazes de discriminar entre o animal conhecido e o desconhecido. No entanto, aos 7 meses de idade, essa capacidade de discriminação é perdida. Tendo como hipótese que a piora na cognição se deve ao agravamento do hipotiroidismo local associado ao estresse do retículo endoplasmático, ao aumento do estresse oxidativo e à neuro inflamação, o objetivo deste trabalho foi avaliar alterações moleculares em camundongos Ala92-D2 aos 7 meses de idade. Para tanto, amostras de hipocampo e córtex pré-frontal de animais Ala92-D2 e Thr92-D2 de 7 meses de idade foram congeladas previamente a -80°C para análise do transcriptoma por RNA sequencing. Os resultados do presente estudo demonstraram que o polimorfismo está associado com alterações no transcriptoma do hipocampo e córtex pré-frontal, com alterações nos genes associados com cognição, memória e neurodesenvolvimento. Além disso, observamos uma redução na densidade neuronal da região CA3 do hipocampo de animais portadores Ala92-D2. Os achados confirmam o polimorfismo Ala92-D2 como um possível fator de risco de declínio cognitivo associado ao envelhecimento.
The Ala92-D2 polymorphism is a genetic mutation in the enzyme that catalyzes the conversion of T4 to T3, the type 2 desiodinase, that is present in a significant portion of the world population (12 to 36%). Ala92-D2 exhibits low catalytic activity, which is associated with the stress of the Endoplasmic Reticulum (ER), memory, and exploratory behavior impairment. Previous results from our laboratory show that memory impairments in Ala92-D2 mice significantly worsen at seven months old. The animal´s performance in the social recognition test is good at 2 months, with the Ala92-D2 animals being able to discriminate between the known and the unknown animal. However, at 7 months old, this ability to discriminate is lost. Considering this data, we hypothesized that the worsening in cognition could be due to the chronification of local hypothyroidism associated with increased oxidative stress and neuroinflammation; the aim of this work is to evaluate molecular changes in Ala92-D2 mice at 7 months old. If the phenotype abnormalities result from local hypothyroidism, short-term treatment with T3 (10 days) should be able to reverse them. To test our hypothesis, samples of the hippocampus, amygdala, striatum, cerebellum, and prefrontal cortex from 7 months old Ala92-D2 and Thr92-D2 mice were frozen at -80°C to perform the analysis of the transcriptome by RNA sequencing. The results of the present study demonstrated that the polymorphism is associated with alterations in the transcriptome of the hippocampus and prefrontal cortex, with changes in genes associated with cognition, memory and neurodevelopment. In addition, we observed a reduction in neuronal density in the CA3 region of the hippocampus of Ala92-D2 carrier animals. The findings confirm the Ala92-D2 polymorphism as a possible risk factor for cognitive decline associated with aging.
The Ala92-D2 polymorphism is a genetic mutation in the enzyme that catalyzes the conversion of T4 to T3, the type 2 desiodinase, that is present in a significant portion of the world population (12 to 36%). Ala92-D2 exhibits low catalytic activity, which is associated with the stress of the Endoplasmic Reticulum (ER), memory, and exploratory behavior impairment. Previous results from our laboratory show that memory impairments in Ala92-D2 mice significantly worsen at seven months old. The animal´s performance in the social recognition test is good at 2 months, with the Ala92-D2 animals being able to discriminate between the known and the unknown animal. However, at 7 months old, this ability to discriminate is lost. Considering this data, we hypothesized that the worsening in cognition could be due to the chronification of local hypothyroidism associated with increased oxidative stress and neuroinflammation; the aim of this work is to evaluate molecular changes in Ala92-D2 mice at 7 months old. If the phenotype abnormalities result from local hypothyroidism, short-term treatment with T3 (10 days) should be able to reverse them. To test our hypothesis, samples of the hippocampus, amygdala, striatum, cerebellum, and prefrontal cortex from 7 months old Ala92-D2 and Thr92-D2 mice were frozen at -80°C to perform the analysis of the transcriptome by RNA sequencing. The results of the present study demonstrated that the polymorphism is associated with alterations in the transcriptome of the hippocampus and prefrontal cortex, with changes in genes associated with cognition, memory and neurodevelopment. In addition, we observed a reduction in neuronal density in the CA3 region of the hippocampus of Ala92-D2 carrier animals. The findings confirm the Ala92-D2 polymorphism as a possible risk factor for cognitive decline associated with aging.
Descrição
Palavras-chave
polimorfismo , hipotireoidismo , memória , Ala92-D2 , desiodase , polymorphism , hypothyroidism , memory , deiodinase