Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, SC, Criciúma, 88806-000, Brazil.
Laboratório de Psiquiatria Translacional, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil.
Metab Brain Dis. 2021 Feb;36(2):247-254. doi: 10.1007/s11011-020-00631-1. Epub 2020 Oct 24.
Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder that affects the activity of the branched-chainα-keto acid dehydrogenase complex (BCDK). This deficiency on BCDK complex results in the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine, and their corresponding α-keto acids. Epigenetic changes can negatively affect the metabolism of BCAA. These changes are catalyzed by the epigenetic regulatory enzymes, e.g., DNA methyltransferase (DNMT), histone deacetylases (HDAC), and histone acetyltransferases (HAT). However, the impacts of BCAA administration on the activity of epigenetic regulatory enzymes in the brain of MSUD patients are still unknown. In this study, we aimed to demonstrate the impact of BCAA administration on the activity of DNMT, HDAC, and HAT in the brain structures of infant rats, an animal model of MSUD. For that, we administered a BCAA pool to infant rats for 21 days. We demonstrated that BCAA administration significantly increased the DNMT and HDAC activities in the hippocampus and striatum, but not in the cerebral cortex of MSUD infant rats. A positive correlation was observed between HDAC and DNMT activities in the hippocampus and striatum of animals exposed to BCAA injections. Our results showed that the BCAA administration could modulate epigenetic regulatory enzymes, mainly DNMT and HDAC, in the brains of infant rats. Therefore, we suggest that the increase in the activity of DNMT and HDAC in the hippocampus and striatum could partially explain the neurological impairments presented in animal models of MSUD.
枫糖尿症（MSUD）是一种常染色体隐性遗传疾病，影响支链α-酮酸脱氢酶复合物（BCDK）的活性。该复合物中 BCDK 的缺乏导致支链氨基酸（BCAA）亮氨酸、异亮氨酸、缬氨酸及其相应的α-酮酸积累。表观遗传变化会对 BCAA 的代谢产生负面影响。这些变化由表观遗传调节酶（例如 DNA 甲基转移酶（DNMT）、组蛋白去乙酰化酶（HDAC）和组蛋白乙酰转移酶（HAT））催化。然而，BCAA 给药对 MSUD 患者大脑中表观遗传调节酶活性的影响尚不清楚。在这项研究中，我们旨在证明 BCAA 给药对 MSUD 幼鼠（MSUD 的动物模型）脑内 DNMT、HDAC 和 HAT 活性的影响。为此，我们在 21 天内给 MSUD 幼鼠施用 BCAA 池。我们证明，BCAA 给药显著增加了 MSUD 幼鼠海马体和纹状体中 DNMT 和 HDAC 的活性，但对大脑皮层没有影响。暴露于 BCAA 注射的动物的海马体和纹状体中的 HDAC 和 DNMT 活性之间观察到正相关。我们的结果表明，BCAA 给药可以调节幼鼠大脑中的表观遗传调节酶，主要是 DNMT 和 HDAC。因此，我们认为海马体和纹状体中 DNMT 和 HDAC 活性的增加部分可以解释 MSUD 动物模型中出现的神经损伤。
