Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ, UK.
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ, UK.
Mol Cell Neurosci. 2020 Dec;109:103553. doi: 10.1016/j.mcn.2020.103553. Epub 2020 Sep 19.
Frontotemporal dementia (FTD) describes a group of clinically heterogeneous conditions that frequently affect people under the age of 65 (Le Ber et al., 2013). There are multiple genetic causes of FTD, including coding or splice-site mutations in MAPT, GRN mutations that lead to haploinsufficiency of progranulin protein, and a hexanucleotide GGGGCC repeat expansion in C9ORF72. Pathologically, FTD is characterised by abnormal protein accumulations in neurons and glia. These aggregates can be composed of the microtubule-associated protein tau (observed in FTD with MAPT mutations), the DNA/RNA-binding protein TDP-43 (seen in FTD with mutations in GRN or C9ORF72 repeat expansions) or dipeptide proteins generated by repeat associated non-ATG translation of the C9ORF72 repeat expansion. There are currently no disease-modifying therapies for FTD and the availability of in vitro models that recapitulate pathologies in a disease-relevant cell type would accelerate the development of novel therapeutics. It is now possible to generate patient-specific stem cells through the reprogramming of somatic cells from a patient with a genotype/phenotype of interest into induced pluripotent stem cells (iPSCs). iPSCs can subsequently be differentiated into a plethora of cell types including neurons, astrocytes and microglia. Using this approach has allowed researchers to generate in vitro models of genetic FTD in human cell types that are largely inaccessible during life. In this review we explore the recent progress in the use of iPSCs to model FTD, and consider the merits, limitations and future prospects of this approach.
额颞叶痴呆（FTD）描述了一组临床上异质的疾病，这些疾病常发生在 65 岁以下的人群中（Le Ber 等人，2013 年）。FTD 有多种遗传原因，包括 MAPT 编码或剪接位点突变、导致颗粒蛋白前体单倍不足的 GRN 突变，以及 C9ORF72 中的六核苷酸 GGGGCC 重复扩展。从病理学上讲，FTD 的特征是神经元和神经胶质中异常蛋白的积累。这些聚集体可以由微管相关蛋白 tau 组成（在携带 MAPT 突变的 FTD 中观察到）、与 DNA/RNA 结合的 TDP-43 蛋白（在携带 GRN 或 C9ORF72 重复扩展突变的 FTD 中观察到）或由 C9ORF72 重复扩展的重复相关非 ATG 翻译产生的二肽蛋白。目前尚无治疗 FTD 的方法，而能够重现相关细胞类型疾病病理学的体外模型将加速新型治疗方法的开发。现在可以通过将患者感兴趣的基因型/表型的体细胞重编程为诱导多能干细胞（iPSC）来生成患者特异性干细胞。iPSC 随后可以分化为多种细胞类型，包括神经元、星形胶质细胞和小胶质细胞。通过这种方法，研究人员能够在体外生成遗传 FTD 的人类细胞类型模型，而这些模型在生命过程中是难以获得的。在这篇综述中，我们探讨了利用 iPSC 来模拟 FTD 的最新进展，并考虑了这种方法的优点、局限性和未来前景。
