High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy

Abstract Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recen...

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Autores principales:	Chialin Cheng, Surya A. Reis, Emily T. Adams, Daniel M. Fass, Steven P. Angus, Timothy J. Stuhlmiller, Jared Richardson, Hailey Olafson, Eric T. Wang, Debasis Patnaik, Roberta L. Beauchamp, Danielle A. Feldman, M. Catarina Silva, Mriganka Sur, Gary L. Johnson, Vijaya Ramesh, Bruce L. Miller, Sally Temple, Kenneth S. Kosik, Bradford C. Dickerson, Stephen J. Haggarty
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dbd7b9c359124c2ab41cec4cd38e2e30
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spelling	oai:doaj.org-article:dbd7b9c359124c2ab41cec4cd38e2e302021-12-02T18:53:19ZHigh-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy10.1038/s41598-021-96227-52045-2322https://doaj.org/article/dbd7b9c359124c2ab41cec4cd38e2e302021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96227-5https://doaj.org/toc/2045-2322Abstract Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recently, a p.A152T tau variant was identified as a risk factor for FTD, Alzheimer's disease, and synucleinopathies. Here we used induced pluripotent stem cells (iPSC) from a patient carrying this p.A152T variant to create a robust, functional cellular assay system for probing pathophysiological tau accumulation and phosphorylation. Using stably transduced iPSC-derived neural progenitor cells engineered to enable inducible expression of the pro-neural transcription factor Neurogenin 2 (Ngn2), we generated disease-relevant, cortical-like glutamatergic neurons in a scalable, high-throughput screening compatible format. Utilizing automated confocal microscopy, and an advanced image-processing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specific effects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to affect tau phosphorylation. These results demonstrate the potential for using patient iPSC-derived ex vivo models of tauopathy as genetically accurate, disease-relevant systems to probe tau biochemistry and support the discovery of novel therapeutics for tauopathies.Chialin ChengSurya A. ReisEmily T. AdamsDaniel M. FassSteven P. AngusTimothy J. StuhlmillerJared RichardsonHailey OlafsonEric T. WangDebasis PatnaikRoberta L. BeauchampDanielle A. FeldmanM. Catarina SilvaMriganka SurGary L. JohnsonVijaya RameshBruce L. MillerSally TempleKenneth S. KosikBradford C. DickersonStephen J. HaggartyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-21 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chialin Cheng Surya A. Reis Emily T. Adams Daniel M. Fass Steven P. Angus Timothy J. Stuhlmiller Jared Richardson Hailey Olafson Eric T. Wang Debasis Patnaik Roberta L. Beauchamp Danielle A. Feldman M. Catarina Silva Mriganka Sur Gary L. Johnson Vijaya Ramesh Bruce L. Miller Sally Temple Kenneth S. Kosik Bradford C. Dickerson Stephen J. Haggarty High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
description	Abstract Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recently, a p.A152T tau variant was identified as a risk factor for FTD, Alzheimer's disease, and synucleinopathies. Here we used induced pluripotent stem cells (iPSC) from a patient carrying this p.A152T variant to create a robust, functional cellular assay system for probing pathophysiological tau accumulation and phosphorylation. Using stably transduced iPSC-derived neural progenitor cells engineered to enable inducible expression of the pro-neural transcription factor Neurogenin 2 (Ngn2), we generated disease-relevant, cortical-like glutamatergic neurons in a scalable, high-throughput screening compatible format. Utilizing automated confocal microscopy, and an advanced image-processing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specific effects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to affect tau phosphorylation. These results demonstrate the potential for using patient iPSC-derived ex vivo models of tauopathy as genetically accurate, disease-relevant systems to probe tau biochemistry and support the discovery of novel therapeutics for tauopathies.
format	article
author	Chialin Cheng Surya A. Reis Emily T. Adams Daniel M. Fass Steven P. Angus Timothy J. Stuhlmiller Jared Richardson Hailey Olafson Eric T. Wang Debasis Patnaik Roberta L. Beauchamp Danielle A. Feldman M. Catarina Silva Mriganka Sur Gary L. Johnson Vijaya Ramesh Bruce L. Miller Sally Temple Kenneth S. Kosik Bradford C. Dickerson Stephen J. Haggarty
author_facet	Chialin Cheng Surya A. Reis Emily T. Adams Daniel M. Fass Steven P. Angus Timothy J. Stuhlmiller Jared Richardson Hailey Olafson Eric T. Wang Debasis Patnaik Roberta L. Beauchamp Danielle A. Feldman M. Catarina Silva Mriganka Sur Gary L. Johnson Vijaya Ramesh Bruce L. Miller Sally Temple Kenneth S. Kosik Bradford C. Dickerson Stephen J. Haggarty
author_sort	Chialin Cheng
title	High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
title_short	High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
title_full	High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
title_fullStr	High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
title_full_unstemmed	High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
title_sort	high-content image-based analysis and proteomic profiling identifies tau phosphorylation inhibitors in a human ipsc-derived glutamatergic neuronal model of tauopathy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dbd7b9c359124c2ab41cec4cd38e2e30
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High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy

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