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.
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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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