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Influence of the genetic polymorphism of type D2 deiodinase (Ala92-D2) on the cognitive functions

Abstract

T4 enters the cells through transporters expressed in the plasma membrane, and will be converted to T3 by deiodinases, the metabolically active form of the hormone. About 12 to 36% of the world population carry a single nucleotide polymorphism (SNP) in the DIO2 gene (rs225014) that expresses type 2 deiodinase (D2), resulting in the Ala92-D2 polymorphism. A recent study published by our group (Jo et al. 2019) shows that male mice carrying Ala92-D2 exhibit moderate memory impairment, less locomotor activity and longer sleep time. Ala92-D2 mice also exhibit less catalytic activity resulting in local hypothyroidism in the striatum, amygdala, prefrontal cortex, hippocampus, and cerebellum, despite being systemically euthyroid. The long-term goal of the present study is to assess whether the aging associated with the Ala92-D2 polymorphism can affect more severely the cognition of animals. Our hypothesis is based on previous unpublished results from our laboratory showing that memory consolidation of 7-month-old male Ala92-D2 mice and 4-month-old Ala92-D2 female is significantly compromised. Our methodological approach will involve the analysis of behavior of the mice and molecular parameters in nuclei of the Central Nervous System, such as the hippocampus, amygdala, and prefrontal cortex of animals. We will also evaluate if T3 can improve to test whether correcting hypothyroidism can reverse the cognitive damage seen in the animals. The behavioral parameters to be studied include the assessment of declarative memory, visual spatial memory, working memory and locomotor activity. Immediately after the behavioral tests, the animals will be sacrificed and the hippocampus, prefrontal cortex and amygdala will be processed to measure the transcriptome using the RNA-sequencing technique. Based on data obtained by transcriptome analysis, we will evaluate the expression of proteins of interest. In addition, we will measure oxidative stress by analyzing antioxidant enzymes, damage to total thiols, carbonyls, and reduced and oxidized glutathione. (AU)

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