Dash M, Eid A, Subaiea G, Chang J, Deeb R, Masoud A, Renehan W E, Adem A, Zawia N H
Interdisciplinary Neurosciences, University of Rhode Island, Kingston, RI, United States.
Interdisciplinary Neurosciences, University of Rhode Island, Kingston, RI, United States; George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, United States.
Neurotoxicology. 2016 Jul;55:154-159. doi: 10.1016/j.neuro.2016.06.001. Epub 2016 Jun 9.
Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of the tau protein in the human brain. The best known of these illnesses is Alzheimer's disease (AD); a disease where the microtubule associated protein tau (MAPT) becomes hyperphosphorylated (lowering its binding affinity to microtubules) and aggregates within neurons in the form of neurofibrillary tangles (NFTs). In this paper we examine whether environmental factors play a significant role in tau pathogenesis. Our studies were conducted in a double mutant mouse model that expressed the human tau gene and lacked the gene for murine tau. The human tau mouse model was tested for the transgene's ability to respond to an environmental toxicant. Pups were developmentally exposed to lead (Pb) from postnatal day (PND) 1-20 with 0.2% Pb acetate. Mice were then sacrificed at PND 20, 30, 40 and 60. Protein and mRNA levels for tau and CDK5 as well as tau phosphorylation at Ser396 were determined. In addition, the potential role of miRNA in tau expression was investigated by measuring levels of miR-34c, a miRNA that targets the mRNA for human tau, at PND20 and 50. The expression of the human tau transgene was altered by developmental exposure to Pb. This exposure also altered the expression of miR-34c. Our findings are the first of their kind to test the responsiveness of the human tau gene to an environmental toxicant and to examine an epigenetic mechanism that may be involved in the regulation of this gene's expression.
tau蛋白病是一类与人类大脑中tau蛋白病理性聚集相关的神经退行性疾病。其中最广为人知的疾病是阿尔茨海默病（AD）；在这种疾病中，微管相关蛋白tau（MAPT）发生过度磷酸化（降低其与微管的结合亲和力）并以神经原纤维缠结（NFTs）的形式在神经元内聚集。在本文中，我们研究环境因素在tau蛋白发病机制中是否起重要作用。我们的研究是在一个双突变小鼠模型中进行的，该模型表达人类tau基因且缺乏鼠tau基因。对人类tau小鼠模型进行测试，以检测转基因对环境毒物的反应能力。从出生后第1天（PND）到第20天，用0.2%醋酸铅对幼崽进行发育性铅（Pb）暴露。然后在PND 20、30、40和60处死小鼠。测定tau和CDK5的蛋白质和mRNA水平以及Ser396处的tau磷酸化水平。此外，通过测量PND20和50时miR-34c（一种靶向人类tau mRNA的miRNA）的水平，研究了miRNA在tau表达中的潜在作用。发育性铅暴露改变了人类tau转基因的表达。这种暴露还改变了miR-34c的表达。我们的发现首次测试了人类tau基因对环境毒物的反应能力，并研究了可能参与该基因表达调控的表观遗传机制。
