Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability
Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauop...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-09-01
|
| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671116301515 |
| id |
doaj-10da84fde5194cf7a648c0db3a201ba1 |
|---|---|
| record_format |
Article |
| spelling |
doaj-10da84fde5194cf7a648c0db3a201ba12020-11-24T23:57:17ZengElsevierStem Cell Reports2213-67112016-09-017332534010.1016/j.stemcr.2016.08.001Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal VulnerabilityM. Catarina Silva0Chialin Cheng1Waltraud Mair2Sandra Almeida3Helen Fong4M. Helal U. Biswas5Zhijun Zhang6Yadong Huang7Sally Temple8Giovanni Coppola9Daniel H. Geschwind10Anna Karydas11Bruce L. Miller12Kenneth S. Kosik13Fen-Biao Gao14Judith A. Steen15Stephen J. Haggarty16Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USADepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USADepartments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USADepartments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USANeural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, NY 12144, USADepartments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USADepartments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USADepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USADepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USADepartment of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USADepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USAFrontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.http://www.sciencedirect.com/science/article/pii/S2213671116301515 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
M. Catarina Silva Chialin Cheng Waltraud Mair Sandra Almeida Helen Fong M. Helal U. Biswas Zhijun Zhang Yadong Huang Sally Temple Giovanni Coppola Daniel H. Geschwind Anna Karydas Bruce L. Miller Kenneth S. Kosik Fen-Biao Gao Judith A. Steen Stephen J. Haggarty |
| spellingShingle |
M. Catarina Silva Chialin Cheng Waltraud Mair Sandra Almeida Helen Fong M. Helal U. Biswas Zhijun Zhang Yadong Huang Sally Temple Giovanni Coppola Daniel H. Geschwind Anna Karydas Bruce L. Miller Kenneth S. Kosik Fen-Biao Gao Judith A. Steen Stephen J. Haggarty Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability Stem Cell Reports |
| author_facet |
M. Catarina Silva Chialin Cheng Waltraud Mair Sandra Almeida Helen Fong M. Helal U. Biswas Zhijun Zhang Yadong Huang Sally Temple Giovanni Coppola Daniel H. Geschwind Anna Karydas Bruce L. Miller Kenneth S. Kosik Fen-Biao Gao Judith A. Steen Stephen J. Haggarty |
| author_sort |
M. Catarina Silva |
| title |
Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability |
| title_short |
Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability |
| title_full |
Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability |
| title_fullStr |
Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability |
| title_full_unstemmed |
Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability |
| title_sort |
human ipsc-derived neuronal model of tau-a152t frontotemporal dementia reveals tau-mediated mechanisms of neuronal vulnerability |
| publisher |
Elsevier |
| series |
Stem Cell Reports |
| issn |
2213-6711 |
| publishDate |
2016-09-01 |
| description |
Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies. |
| url |
http://www.sciencedirect.com/science/article/pii/S2213671116301515 |
| work_keys_str_mv |
AT mcatarinasilva humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT chialincheng humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT waltraudmair humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT sandraalmeida humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT helenfong humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT mhelalubiswas humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT zhijunzhang humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT yadonghuang humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT sallytemple humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT giovannicoppola humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT danielhgeschwind humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT annakarydas humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT brucelmiller humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT kennethskosik humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT fenbiaogao humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT judithasteen humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability AT stephenjhaggarty humanipscderivedneuronalmodeloftaua152tfrontotemporaldementiarevealstaumediatedmechanismsofneuronalvulnerability |
| _version_ |
1725454687744819200 |