ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discov...

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Published in	Cell Vol. 184; no. 17; pp. 4547 - 4563.e17
Main Authors	Bowles, Kathryn R., Silva, M. Catarina, Whitney, Kristen, Bertucci, Taylor, Berlind, Joshua E., Lai, Jesse D., Garza, Jacob C., Boles, Nathan C., Mahali, Sidhartha, Strang, Kevin H., Marsh, Jacob A., Chen, Cynthia, Pugh, Derian A., Liu, Yiyuan, Gordon, Ronald E., Goderie, Susan K., Chowdhury, Rebecca, Lotz, Steven, Lane, Keith, Crary, John F., Haggarty, Stephen J., Karch, Celeste M., Ichida, Justin K., Goate, Alison M., Temple, Sally
Format	Journal Article
Language	English
Published	United States Elsevier Inc 19.08.2021
Subjects	autophagy Autophagy - drug effects Autophagy - genetics Biomarkers - metabolism Body Patterning - drug effects Body Patterning - genetics Cell Death - drug effects Cell Line Cerebrum - pathology death dementia ELAV-Like Protein 4 - genetics ELAVL4 frontotemporal dementia glutamatergic neurons glutamic acid Glutamic Acid - metabolism Humans Hydrazones - pharmacology Lysosomes - drug effects Lysosomes - metabolism MAPT Morpholines - pharmacology mutants mutation Mutation - genetics neurodegenerative diseases neurons Neurons - drug effects Neurons - metabolism Neurons - pathology organoids Organoids - drug effects Organoids - metabolism Organoids - ultrastructure Phosphorylation - drug effects Pyrimidines - pharmacology RNA Splicing - drug effects RNA Splicing - genetics RNA-binding proteins Signal Transduction - drug effects splicing stem cells Stress Granules - drug effects Stress Granules - metabolism Synapses - metabolism synaptic signaling tau Proteins - genetics tauopathy therapeutics toxicity Up-Regulation - drug effects Up-Regulation - genetics synaptic signaling tauopathy autophagy organoids ELAVL4 frontotemporal dementia MAPT splicing glutamatergic neurons
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Abstract	Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. [Display omitted] •Tau and P-tau accumulation and autophagy disruption in tau-V337M organoids•Accelerated synaptic maturation and loss of glutamatergic cortical-layer neurons•Altered ELAVL4 expression, dysregulated splicing, accelerated synaptic maturation•Rescue of susceptibility to glutamatergic toxicity by PIKFYVE inhibitor apilimod Characterization of iPSC-derived cerebral organoids with the tau-V337M mutation, which causes frontotemporal dementia, reveals changes preceding neuron death as potential targets for therapeutic intervention, as demonstrated by rescue of susceptibility to glutamatergic toxicity by the PIKFYVE inhibitor apilimod.
AbstractList	Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. [Display omitted] •Tau and P-tau accumulation and autophagy disruption in tau-V337M organoids•Accelerated synaptic maturation and loss of glutamatergic cortical-layer neurons•Altered ELAVL4 expression, dysregulated splicing, accelerated synaptic maturation•Rescue of susceptibility to glutamatergic toxicity by PIKFYVE inhibitor apilimod Characterization of iPSC-derived cerebral organoids with the tau-V337M mutation, which causes frontotemporal dementia, reveals changes preceding neuron death as potential targets for therapeutic intervention, as demonstrated by rescue of susceptibility to glutamatergic toxicity by the PIKFYVE inhibitor apilimod. Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT , glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4 , and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. Characterization of iPSC-derived cerebral organoids with the tau-V337M mutation, which causes frontotemporal dementia, reveals changes preceding neuron death as potential targets for therapeutic intervention, as demonstrated by rescue of susceptibility to glutamatergic toxicity by the PIKFYVE inhibitor apilimod. Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
Author	Pugh, Derian A. Lotz, Steven Liu, Yiyuan Gordon, Ronald E. Silva, M. Catarina Marsh, Jacob A. Lane, Keith Garza, Jacob C. Bertucci, Taylor Boles, Nathan C. Ichida, Justin K. Haggarty, Stephen J. Goate, Alison M. Whitney, Kristen Bowles, Kathryn R. Strang, Kevin H. Chen, Cynthia Mahali, Sidhartha Goderie, Susan K. Temple, Sally Chowdhury, Rebecca Lai, Jesse D. Berlind, Joshua E. Karch, Celeste M. Crary, John F.
AuthorAffiliation	1 Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA 3 Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA 2 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA 9 Lead contact 8 Senior author 6 Amgen Research, One Amgen Center Dr., Thousand Oaks, CA 91320, USA 4 Neural Stem Cell Institute, Rensselaer, NY 12144, USA 5 Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA 7 Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA
AuthorAffiliation_xml	– name: 5 Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA – name: 8 Senior author – name: 6 Amgen Research, One Amgen Center Dr., Thousand Oaks, CA 91320, USA – name: 9 Lead contact – name: 3 Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA – name: 1 Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA – name: 7 Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA – name: 2 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – name: 4 Neural Stem Cell Institute, Rensselaer, NY 12144, USA
Author_xml	– sequence: 1 givenname: Kathryn R. surname: Bowles fullname: Bowles, Kathryn R. organization: Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA – sequence: 2 givenname: M. Catarina surname: Silva fullname: Silva, M. Catarina organization: Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 3 givenname: Kristen surname: Whitney fullname: Whitney, Kristen organization: Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA – sequence: 4 givenname: Taylor surname: Bertucci fullname: Bertucci, Taylor organization: Neural Stem Cell Institute, Rensselaer, NY 12144, USA – sequence: 5 givenname: Joshua E. surname: Berlind fullname: Berlind, Joshua E. organization: Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA – sequence: 6 givenname: Jesse D. surname: Lai fullname: Lai, Jesse D. organization: Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA – sequence: 7 givenname: Jacob C. surname: Garza fullname: Garza, Jacob C. organization: Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 8 givenname: Nathan C. surname: Boles fullname: Boles, Nathan C. organization: Neural Stem Cell Institute, Rensselaer, NY 12144, USA – sequence: 9 givenname: Sidhartha surname: Mahali fullname: Mahali, Sidhartha organization: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA – sequence: 10 givenname: Kevin H. surname: Strang fullname: Strang, Kevin H. organization: Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA – sequence: 11 givenname: Jacob A. surname: Marsh fullname: Marsh, Jacob A. organization: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA – sequence: 12 givenname: Cynthia surname: Chen fullname: Chen, Cynthia organization: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA – sequence: 13 givenname: Derian A. surname: Pugh fullname: Pugh, Derian A. organization: Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA – sequence: 14 givenname: Yiyuan surname: Liu fullname: Liu, Yiyuan organization: Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA – sequence: 15 givenname: Ronald E. surname: Gordon fullname: Gordon, Ronald E. organization: Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA – sequence: 16 givenname: Susan K. surname: Goderie fullname: Goderie, Susan K. organization: Neural Stem Cell Institute, Rensselaer, NY 12144, USA – sequence: 17 givenname: Rebecca surname: Chowdhury fullname: Chowdhury, Rebecca organization: Neural Stem Cell Institute, Rensselaer, NY 12144, USA – sequence: 18 givenname: Steven surname: Lotz fullname: Lotz, Steven organization: Neural Stem Cell Institute, Rensselaer, NY 12144, USA – sequence: 19 givenname: Keith surname: Lane fullname: Lane, Keith organization: Neural Stem Cell Institute, Rensselaer, NY 12144, USA – sequence: 20 givenname: John F. surname: Crary fullname: Crary, John F. organization: Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, USA – sequence: 21 givenname: Stephen J. surname: Haggarty fullname: Haggarty, Stephen J. organization: Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA – sequence: 22 givenname: Celeste M. surname: Karch fullname: Karch, Celeste M. organization: Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA – sequence: 23 givenname: Justin K. surname: Ichida fullname: Ichida, Justin K. organization: Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA – sequence: 24 givenname: Alison M. surname: Goate fullname: Goate, Alison M. email: alison.goate@mssm.edu organization: Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, USA – sequence: 25 givenname: Sally surname: Temple fullname: Temple, Sally email: sallytemple@neuralsci.org organization: Neural Stem Cell Institute, Rensselaer, NY 12144, USA
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Keywords	synaptic signaling tauopathy autophagy organoids ELAVL4 frontotemporal dementia MAPT splicing glutamatergic neurons
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Snippet	Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms.... Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms....
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SubjectTerms	autophagy Autophagy - drug effects Autophagy - genetics Biomarkers - metabolism Body Patterning - drug effects Body Patterning - genetics Cell Death - drug effects Cell Line Cerebrum - pathology death dementia ELAV-Like Protein 4 - genetics ELAVL4 frontotemporal dementia glutamatergic neurons glutamic acid Glutamic Acid - metabolism Humans Hydrazones - pharmacology Lysosomes - drug effects Lysosomes - metabolism MAPT Morpholines - pharmacology mutants mutation Mutation - genetics neurodegenerative diseases neurons Neurons - drug effects Neurons - metabolism Neurons - pathology organoids Organoids - drug effects Organoids - metabolism Organoids - ultrastructure Phosphorylation - drug effects Pyrimidines - pharmacology RNA Splicing - drug effects RNA Splicing - genetics RNA-binding proteins Signal Transduction - drug effects splicing stem cells Stress Granules - drug effects Stress Granules - metabolism Synapses - metabolism synaptic signaling tau Proteins - genetics tauopathy therapeutics toxicity Up-Regulation - drug effects Up-Regulation - genetics
Title	ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids
URI	https://dx.doi.org/10.1016/j.cell.2021.07.003 https://www.ncbi.nlm.nih.gov/pubmed/34314701 https://www.proquest.com/docview/2555967572 https://www.proquest.com/docview/2636533740 https://pubmed.ncbi.nlm.nih.gov/PMC8635409
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