Kopach, O;
Esteras, N;
Wray, S;
Abramov, AY;
Rusakov, DA;
(2021)
Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia.
Cell Death & Disease
, 12
(8)
, Article 716. 10.1038/s41419-021-04007-w.
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Abstract
Human iPSC lines represent a powerful translational model of tauopathies. We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the MAPT 10+16 splice-site mutation. This mutation leads to the increased splicing of 4R tau isoforms. However, the role of different isoforms of tau protein in initiating neuronal dementia-related dysfunction, and the causality between the MAPT 10+16 mutation and altered neuronal activity have remained unclear. Here, we employed genetically engineered cells, in which the IVS10+16 mutation was introduced into healthy donor iPSCs to increase the expression of 4R tau isoform in exon 10, aiming to explore key physiological traits of iPSC-derived MAPT IVS10+16 neurons using patch-clamp electrophysiology and multiphoton fluorescent imaging techniques. We found that during late in vitro neurogenesis (from ~180 to 230 days) iPSC-derived cortical neurons of the control group (parental wild-type tau) exhibited membrane properties compatible with "mature" neurons. In contrast, MAPT IVS10+16 neurons displayed impaired excitability, as reflected by a depolarized resting membrane potential, an increased input resistance, and reduced voltage-gated Na+- and K+-channel-mediated currents. The mutation changed the channel properties of fast-inactivating Nav and decreased the Nav1.6 protein level. MAPT IVS10+16 neurons exhibited reduced firing accompanied by a changed action potential waveform and severely disturbed intracellular Ca2+ dynamics, both in the soma and dendrites, upon neuronal depolarization. These results unveil a causal link between the MAPT 10+16 mutation, hence overproduction of 4R tau, and a dysfunction of human cells, identifying a biophysical basis of changed neuronal activity in 4R tau-triggered dementia. Our study lends further support to using iPSC lines as a suitable platform for modelling tau-induced human neuropathology in vitro.
| Type: | Article |
|---|---|
| Title: | Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41419-021-04007-w |
| Publisher version: | https://doi.org/10.1038/s41419-021-04007-w |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10131895 |
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