Silva M Catarina, Cheng Chialin, Mair Waltraud, Almeida Sandra, Fong Helen, Biswas M Helal U, Zhang Zhijun, Huang Yadong, Temple Sally, Coppola Giovanni, Geschwind Daniel H, Karydas Anna, Miller Bruce L, Kosik Kenneth S, Gao Fen-Biao, Steen Judith A, Haggarty Stephen J
Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Stem Cell Reports. 2016 Sep 13;7(3):325-340. doi: 10.1016/j.stemcr.2016.08.001. Epub 2016 Sep 1.
Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.
额颞叶痴呆（FTD）和其他以局灶性脑神经元变性和蛋白质病理性积聚为特征的tau蛋白病通常与tau基因突变有关。然而，神经元丢失的机制尚未完全明确。为了确定与tau蛋白病相关的分子事件，我们研究了携带tau-A152T变异体个体的诱导多能干细胞（iPSC）衍生神经元。我们强调了人类神经元细胞模型深入表型分析在临床前研究和鉴定内源性tau毒性调节剂方面的潜力。通过一系列生化和细胞分析，A152T神经元显示出tau蛋白的积聚、重新分布和溶解度降低。tau蛋白的上调与应激诱导标志物的增强以及细胞对蛋白毒性、兴奋性毒性和线粒体应激源的易感性增加相关，这在CRISPR/Cas9介导的tau蛋白靶向或自噬的药理学激活后得到挽救。我们的研究结果揭示了tau蛋白介导的与神经元易感性相关的特定途径的扰动，揭示了FTD和其他tau蛋白病潜在的早期疾病生物标志物和治疗靶点。
