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Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons

Capano, LS; Sato, C; Ficulle, E; Yu, A; Horie, K; Kwon, JS; Burbach, KF; ... Yoo, AS; + view all (2022) Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons. Cell Stem Cell , 29 (6) 918-932.e8. 10.1016/j.stem.2022.04.018. Green open access

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Abstract

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.

Type: Article
Title: Recapitulation of endogenous 4R tau expression and formation of insoluble tau in directly reprogrammed human neurons
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.stem.2022.04.018
Publisher version: https://doi.org/10.1016/j.stem.2022.04.018
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell & Tissue Engineering, Cell Biology, FRONTOTEMPORAL DEMENTIA, HUMAN FIBROBLASTS, PROTEIN-TAU, DIRECT CONVERSION, GENE-EXPRESSION, ISOFORM, GENERATION, MUTATIONS, FATE, NEUROPATHOLOGY
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10152372
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