Gamir-Morralla Andrea, Sacristán Sandra, Medina Miguel, Iglesias Teresa
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
J Alzheimers Dis Rep. 2019 Feb 16;3(1):47-57. doi: 10.3233/ADR-180087.
The nematode is a powerful model organism to study lifespan and aging, protein aggregation, and neurodegeneration, as well as to carry out drug screenings. The strain /T337 expresses human pathogenic V337M mutant tau under a pan-neuronal promoter and presents uncoordinated locomotion, accumulation of phosphorylated insoluble tau, and shortened lifespan. Herein we have used this strain to assay two compounds that could affect tau aggregation and/or phosphorylation, and looked for phenotypic changes in their lifespan and motility. The first compound is Thioflavin T (ThT), a member of the tetracycline family with protein antiaggregant properties, yet to be tested in a tauopathy model. The second is a novel small molecule, NP103, a highly selective inhibitor of glycogen synthase kinase-3 (GSK-3), the main kinase contributing to pathogenic tau hyperphosphorylation. Importantly, we find that ThT extends lifespan of /T337 worms as it does with control N2 animals, showing both strains similar locomotion features under this treatment. By contrast, NP103 improves the paralysis phenotype of /T337 mutants but not their lifespan. Our results show that both treatments present beneficial effects for this model of tauopathy and encourage pursuing further investigations on their therapeutic potential for AD and other tauopathies.
线虫是研究寿命与衰老、蛋白质聚集和神经退行性变以及进行药物筛选的一种强大的模式生物。/T337品系在全神经元启动子的控制下表达人类致病性V337M突变型tau蛋白，表现出运动不协调、磷酸化不溶性tau蛋白的积累以及寿命缩短。在此，我们使用该品系来检测两种可能影响tau蛋白聚集和/或磷酸化的化合物，并寻找它们在寿命和运动能力方面的表型变化。第一种化合物是硫黄素T（ThT），它是四环素家族的一员，具有蛋白质抗聚集特性，但尚未在tau蛋白病模型中进行测试。第二种是一种新型小分子NP103，它是糖原合酶激酶-3（GSK-3）的高度选择性抑制剂，GSK-3是导致致病性tau蛋白过度磷酸化的主要激酶。重要的是，我们发现ThT能延长/T337线虫的寿命，就像它对对照N2动物所起的作用一样，在这种处理下两种品系表现出相似的运动特征。相比之下，NP103改善了/T337突变体的麻痹表型，但没有延长它们的寿命。我们的结果表明，这两种处理方法对这种tau蛋白病模型都有有益的影响，并鼓励进一步研究它们对阿尔茨海默病和其他tau蛋白病的治疗潜力。
