Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Program in Molecular and Cell Biology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Stem Cell. 2022 Jun 2;29(6):918-932.e8. doi: 10.1016/j.stem.2022.04.018.
Tau is a microtubule-binding protein expressed in neurons, and the equal ratios between 4-repeat (4R) and 3-repeat (3R) isoforms are maintained in normal adult brain function. Dysregulation of 3R:4R ratio causes tauopathy, and human neurons that recapitulate tau isoforms in health and disease will provide a platform for elucidating pathogenic processes involving tau pathology. We carried out extensive characterizations of tau isoforms expressed in human neurons derived by microRNA-induced neuronal reprogramming of adult fibroblasts. Transcript and protein analyses showed that miR neurons expressed all six isoforms with the 3R:4R isoform ratio equivalent to that detected in human adult brains. Also, miR neurons derived from familial tauopathy patients with a 3R:4R ratio altering mutation showed increased 4R tau and the formation of insoluble tau with seeding activity. Our results collectively demonstrate the utility of miRNA-induced neuronal reprogramming to recapitulate endogenous tau regulation comparable with the adult brain in health and disease.
Tau 是一种在神经元中表达的微管结合蛋白，正常成年大脑功能中维持着 4 重复（4R）和 3 重复（3R）异构体的比例相等。3R：4R 比值的失调会导致 tau 病， recapitulate tau 异构体的健康和疾病人类神经元将为阐明涉及 tau 病理学的致病过程提供一个平台。我们对通过成年成纤维细胞的 microRNA 诱导神经元重编程表达的人类神经元中的 tau 异构体进行了广泛的表征。转录本和蛋白质分析表明，miR 神经元表达了所有六种异构体，其 3R：4R 异构体比例与在人类成年大脑中检测到的比例相当。此外，源自携带 3R：4R 比值改变突变的家族性 tau 病患者的 miR 神经元显示出增加的 4R tau 和具有种子活性的不溶性 tau 的形成。我们的结果共同证明了使用 microRNA 诱导的神经元重编程来重现与健康和疾病成人大脑相当的内源性 tau 调节的实用性。
