Kühn Rebekka, Mahajan Aayushi, Canoll Peter, Hargus Gunnar
Department of Pathology and Cell Biology, Columbia University, New York, NY, United States.
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States.
Front Cell Dev Biol. 2021 Nov 10;9:766773. doi: 10.3389/fcell.2021.766773. eCollection 2021.
Neurodegenerative dementias are the most common group of neurodegenerative diseases affecting more than 40 million people worldwide. One of these diseases is frontotemporal dementia (FTD), an early onset dementia and one of the leading causes of dementia in people under the age of 60. FTD is a heterogeneous group of neurodegenerative disorders with pathological accumulation of particular proteins in neurons and glial cells including the microtubule-associated protein tau, which is deposited in its hyperphosphorylated form in about half of all patients with FTD. As for other patients with dementia, there is currently no cure for patients with FTD and thus several lines of research focus on the characterization of underlying pathogenic mechanisms with the goal to identify therapeutic targets. In this review, we provide an overview of reported disease phenotypes in induced pluripotent stem cell (iPSC)-derived neurons and glial cells from patients with tau-associated FTD with the aim to highlight recent progress in this fast-moving field of iPSC disease modeling. We put a particular focus on genetic forms of the disease that are linked to mutations in the gene encoding tau and summarize mutation-associated changes in FTD patient cells related to tau splicing and tau phosphorylation, microtubule function and cell metabolism as well as calcium homeostasis and cellular stress. In addition, we discuss challenges and limitations but also opportunities using differentiated patient-derived iPSCs for disease modeling and biomedical research on neurodegenerative diseases including FTD.
神经退行性痴呆是最常见的神经退行性疾病组，全球有超过4000万人受其影响。其中一种疾病是额颞叶痴呆（FTD），这是一种早发性痴呆，也是60岁以下人群痴呆的主要原因之一。FTD是一组异质性神经退行性疾病，其特征是特定蛋白质在神经元和神经胶质细胞中病理性积聚，包括微管相关蛋白tau，约一半的FTD患者中tau以其过度磷酸化形式沉积。与其他痴呆患者一样，目前FTD患者尚无治愈方法，因此有几条研究路线集中在潜在致病机制的表征上，目标是确定治疗靶点。在本综述中，我们概述了来自tau相关FTD患者的诱导多能干细胞（iPSC）衍生的神经元和神经胶质细胞中报告的疾病表型，旨在突出iPSC疾病建模这一快速发展领域的最新进展。我们特别关注与tau编码基因突变相关的疾病遗传形式，并总结FTD患者细胞中与tau剪接和tau磷酸化、微管功能和细胞代谢以及钙稳态和细胞应激相关的突变相关变化。此外，我们讨论了使用分化的患者来源iPSC进行疾病建模和包括FTD在内的神经退行性疾病生物医学研究的挑战、局限性以及机遇。
