High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/138330 |
| _version_ | 1811086001920016384 |
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| author | Cheng, Chialin Reis, Surya A Adams, Emily T Fass, Daniel M Angus, Steven P Stuhlmiller, Timothy J Richardson, Jared Olafson, Hailey Wang, Eric T Patnaik, Debasis Beauchamp, Roberta L Feldman, Danielle A Silva, M Catarina Sur, Mriganka Johnson, Gary L Ramesh, Vijaya Miller, Bruce L Temple, Sally Kosik, Kenneth S Dickerson, Bradford C Haggarty, Stephen J |
| author2 | Picower Institute for Learning and Memory |
| author_facet | Picower Institute for Learning and Memory Cheng, Chialin Reis, Surya A Adams, Emily T Fass, Daniel M Angus, Steven P Stuhlmiller, Timothy J Richardson, Jared Olafson, Hailey Wang, Eric T Patnaik, Debasis Beauchamp, Roberta L Feldman, Danielle A Silva, M Catarina Sur, Mriganka Johnson, Gary L Ramesh, Vijaya Miller, Bruce L Temple, Sally Kosik, Kenneth S Dickerson, Bradford C Haggarty, Stephen J |
| author_sort | Cheng, Chialin |
| collection | MIT |
| description | 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 identifed 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 imageprocessing pipeline optimized for analysis of morphologically complex human neuronal cultures,
we report quantitative, subcellular localization-specifc efects of multiple kinase inhibitors on tau,
including ones under clinical investigation not previously reported to afect 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. |
| first_indexed | 2024-09-23T13:19:20Z |
| format | Article |
| id | mit-1721.1/138330 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:19:20Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1383302023-12-08T18:07:09Z High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy Cheng, Chialin Reis, Surya A Adams, Emily T Fass, Daniel M Angus, Steven P Stuhlmiller, Timothy J Richardson, Jared Olafson, Hailey Wang, Eric T Patnaik, Debasis Beauchamp, Roberta L Feldman, Danielle A Silva, M Catarina Sur, Mriganka Johnson, Gary L Ramesh, Vijaya Miller, Bruce L Temple, Sally Kosik, Kenneth S Dickerson, Bradford C Haggarty, Stephen J Picower Institute for Learning and Memory 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 identifed 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 imageprocessing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specifc efects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to afect 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. 2021-12-06T17:52:42Z 2021-12-06T17:52:42Z 2021-12 2021-12-06T17:45:30Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/138330 Cheng, Chialin, Reis, Surya A, Adams, Emily T, Fass, Daniel M, Angus, Steven P et al. 2021. "High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy." Scientific Reports, 11 (1). en 10.1038/s41598-021-96227-5 Scientific Reports Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Scientific Reports |
| spellingShingle | Cheng, Chialin Reis, Surya A Adams, Emily T Fass, Daniel M Angus, Steven P Stuhlmiller, Timothy J Richardson, Jared Olafson, Hailey Wang, Eric T Patnaik, Debasis Beauchamp, Roberta L Feldman, Danielle A Silva, M Catarina Sur, Mriganka Johnson, Gary L Ramesh, Vijaya Miller, Bruce L Temple, Sally Kosik, Kenneth S Dickerson, Bradford C Haggarty, Stephen J High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy |
| title | 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_short | 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 |
| url | https://hdl.handle.net/1721.1/138330 |
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