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

Kathryn R. Bowles; M. Catarina Silva; Kristen Whitney; Taylor Bertucci; Joshua E. Berlind; Jesse D. Lai; Jacob C. Garza; Nathan C. Boles; Sidhartha Mahali; Kevin H. Strang; Jacob A. Marsh; Cynthia Chen; Derian A. Pugh; Yiyuan Liu; Ronald E. Gordon; Susan K. Goderie; Rebecca Chowdhury; Steven Lotz; Keith Lane; John F. Crary; Stephen J. Haggarty; Celeste M. Karch; Justin K. Ichida; Alison M. Goate; Sally Temple

doi:10.1016/j.cell.2021.07.003

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

Kathryn R. Bowles, M. Catarina Silva, Kristen Whitney, Taylor Bertucci, Joshua E. Berlind, Jesse D. Lai, Jacob C. Garza, Nathan C. Boles, Sidhartha Mahali, Kevin H. Strang, Jacob A. Marsh, Cynthia Chen, Derian A. Pugh, Yiyuan Liu, Ronald E. Gordon, Susan K. Goderie, Rebecca Chowdhury, Steven Lotz, Keith Lane, John F. CraryStephen J. Haggarty, Celeste M. Karch, Justin K. Ichida, Alison M. Goate, Sally Temple

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English
Pages (from-to)	4547-4563.e17
Journal	Cell
Volume	184
Issue number	17
DOIs	https://doi.org/10.1016/j.cell.2021.07.003
State	Published - 19 Aug 2021

Keywords

ELAVL4
MAPT
autophagy
frontotemporal dementia
glutamatergic neurons
organoids
splicing
synaptic signaling
tauopathy

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10.1016/j.cell.2021.07.003

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Bowles, K. R., Silva, M. C., Whitney, K., Bertucci, T., Berlind, J. E., Lai, J. D., Garza, J. C., Boles, N. C., Mahali, S., Strang, K. H., Marsh, J. A., Chen, C., Pugh, D. A., Liu, Y., Gordon, R. E., Goderie, S. K., Chowdhury, R., Lotz, S., Lane, K., ... Temple, S. (2021). ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell, 184(17), 4547-4563.e17. https://doi.org/10.1016/j.cell.2021.07.003

@article{0e8e95c85c7d4316a5e6cf0c810d6406,

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

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.",

keywords = "ELAVL4, MAPT, autophagy, frontotemporal dementia, glutamatergic neurons, organoids, splicing, synaptic signaling, tauopathy",

author = "Bowles, {Kathryn R.} and Silva, {M. Catarina} and Kristen Whitney and Taylor Bertucci and Berlind, {Joshua E.} and Lai, {Jesse D.} and Garza, {Jacob C.} and Boles, {Nathan C.} and Sidhartha Mahali and Strang, {Kevin H.} and Marsh, {Jacob A.} and Cynthia Chen and Pugh, {Derian A.} and Yiyuan Liu and Gordon, {Ronald E.} and Goderie, {Susan K.} and Rebecca Chowdhury and Steven Lotz and Keith Lane and Crary, {John F.} and Haggarty, {Stephen J.} and Karch, {Celeste M.} and Ichida, {Justin K.} and Goate, {Alison M.} and Sally Temple",

note = "Funding Information: We are grateful to the Tau Consortium and Rainwater Charitable Foundation for supporting this project, CurePSP for protocol development support, and the New York Genome Center for scRNA-seq expertise. We thank the research subjects and their families for their generous participation, including in ARTFL (U54NS092089) and LEFFTDS (U01AG045390), and support staff at participating sites. We thank Shawn Sutton, Brian Unruh, Isabel Tian, Khadijah Onanuga, and Nicholas St. John at the NeuraCell core facility (https://www.neuracell.org/) for organoid production; the ISMMS Neuropathology Brain Bank & Research Core for technical assistance and Aaron Bell for sample preparation; and the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine for equipment access. Elements of Figures 1A and 2B and the graphical abstract were created with BioRender. This work was supported by the Tau Consortium; the Rainwater Charitable Foundation (to C.M.K. J.F.C. S.J.H. J.K.I. A.M.G. and S.T.); NIH AG046374 (to C.M.K.); CurePSP (to K.R.B.); the MGH Research Scholars Program (to S.J.H.); the Association for Frontotemporal Degeneration (AFTD; to M.C.S. and K.R.B.); the BrightFocus Foundation (to K.R.B.); the Farrell Family Alzheimer's Disease Research Fund; NIH NS110890 (to C.M.K.); NIH R01AG054008 and R01NS095252 (to J.F.C.); NIH/NINDS R35 NS097277 (to S.T.); NIH/NIA R01 AG056293 (to S.T. and C.M.K.); NIH 2R01NS097850; Department of Defense W81XWH-21-1-0168, W81XWH-20-1-0424, and W81XWH-21-1-0131; the Harrington Discovery Institute; CIRM, the ALS Association; the John Douglas French Alzheimer's Foundation; ADDF, the New York Stem Cell Foundation (to J.K.I.); an Amgen postdoctoral fellowship (to J.D.L.); and NIH NINDS/NIA F31NS117075 (to J.E.B.). Neuracell received support from the Empire State Stem Cell Fund (NYSTEM) through New York State Department of Health contract C029158. Opinions expressed here are solely those of the authors and do not necessarily reflect those of the Empire State Stem Cell Board, the New York State Department of Health, or the State of New York. Conceptualization, K.R.B. M.C.S. J.C.G. C.M.K. J.K.I. S.J.H. J.F.C. A.M.G. and S.T.; methodology, K.R.B. M.C.S. J.C.G. K.H.S. K.W. S.K.G. S.L. K.L. J.K.I. S.M. J.F.C. C.M.K. D.A.P. N.C.B. T.B. and R.C.; software, K.R.B. K.W. and N.C.B.; formal analysis, K.R.B. K.W. T.B. J.C.G. J.E.B. J.D.L. J.K.I. S.M. C.M.K. Y.L. N.C.B. R.E.G. and S.K.G.; investigation, K.R.B. M.C.S. T.B. J.C.G. K.H.S. K.W. S.M. J.A.M. C.C. J.E.B. J.D.L. and R.C.; resources, K.W. S.K.G. J.E.B. J.D.L. S.L. J.K.I. C.M.K. and S.T.; data curation, K.R.B. K.W. and T.B.; writing – original draft, K.R.B. M.C.S. and T.B.; writing – review & editing, K.R.B. M.C.S. C.M.K. J.K.I. S.J.H. J.F.C. A.M.G. S.T. K.W. S.M. and R.C.; supervision, C.M.K. J.K.I. S.J.H. J.F.C. A.M.G. and S.T.; project administration, S.K.G. S.L. A.M.G. T.B. and S.T.; funding acquisition, K.R.B. M.C.S. C.M.K. J.K.I. S.J.H. A.M.G. and S.T. J.D.L. employee, Amgen. A.M.G.: Scientific Advisory Board (SAB), Denali Therapeutics (2015–2018); Genetic SAB, Pfizer (2019); SAB, Genentech; consultant, GSK, AbbVie, Biogen, and Eisai. S.J.H.: SAB, Rodin Therapeutics, Frequency Therapeutics, Psy Therapeutics, Vesigen Therapeutics, and Souvien Therapeutics; inventor, patent 6,475,723. S.T.: president, StemCultures; cofounder, LUXA Biotech; SAB, Sana Biotechnology, Blue Rock Therapeutics, and Vita Therapeutics; inventor, patent 16/331,063. J.K.I.: cofounder, AcuraStem and Modulo Bio; SAB, Spinogenix. Named companies were not involved in this project. Funding Information: We are grateful to the Tau Consortium and Rainwater Charitable Foundation for supporting this project, CurePSP for protocol development support, and the New York Genome Center for scRNA-seq expertise. We thank the research subjects and their families for their generous participation, including in ARTFL ( U54NS092089 ) and LEFFTDS ( U01AG045390 ), and support staff at participating sites. We thank Shawn Sutton, Brian Unruh, Isabel Tian, Khadijah Onanuga, and Nicholas St. John at the NeuraCell core facility ( https://www.neuracell.org/ ) for organoid production; the ISMMS Neuropathology Brain Bank & Research Core for technical assistance and Aaron Bell for sample preparation; and the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine for equipment access. Elements of Figures 1 A and 2 B and the graphical abstract were created with BioRender. This work was supported by the Tau Consortium ; the Rainwater Charitable Foundation (to C.M.K., J.F.C., S.J.H., J.K.I., A.M.G., and S.T.); NIH AG046374 (to C.M.K.); CurePSP (to K.R.B.); the MGH Research Scholars Program (to S.J.H.); the Association for Frontotemporal Degeneration (AFTD; to M.C.S. and K.R.B.); the BrightFocus Foundation (to K.R.B.); the Farrell Family Alzheimer{\textquoteright}s Disease Research Fund ; NIH NS110890 (to C.M.K.); NIH R01AG054008 and R01NS095252 (to J.F.C.); NIH /NINDS R35 NS097277 (to S.T.); NIH /NIA R01 AG056293 (to S.T. and C.M.K.); NIH 2R01NS097850 ; Department of Defense W81XWH-21-1-0168 , W81XWH-20-1-0424 , and W81XWH-21-1-0131 ; the Harrington Discovery Institute ; CIRM , the ALS Association ; the John Douglas French Alzheimer{\textquoteright}s Foundation ; ADDF , the New York Stem Cell Foundation (to J.K.I.); an Amgen postdoctoral fellowship (to J.D.L.); and NIH NINDS /NIA F31NS117075 (to J.E.B.). Neuracell received support from the Empire State Stem Cell Fund (NYSTEM) through New York State Department of Health contract C029158 . Opinions expressed here are solely those of the authors and do not necessarily reflect those of the Empire State Stem Cell Board, the New York State Department of Health, or the State of New York. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = aug,

day = "19",

doi = "10.1016/j.cell.2021.07.003",

language = "English",

volume = "184",

pages = "4547--4563.e17",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "17",

}

Bowles, KR, Silva, MC, Whitney, K, Bertucci, T, Berlind, JE, Lai, JD, Garza, JC, Boles, NC, Mahali, S, Strang, KH, Marsh, JA, Chen, C, Pugh, DA, Liu, Y, Gordon, RE, Goderie, SK, Chowdhury, R, Lotz, S, Lane, K, Crary, JF, Haggarty, SJ, Karch, CM, Ichida, JK, Goate, AM & Temple, S 2021, 'ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids', Cell, vol. 184, no. 17, pp. 4547-4563.e17. https://doi.org/10.1016/j.cell.2021.07.003

TY - JOUR

T1 - ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids

AU - Bowles, Kathryn R.

AU - Silva, M. Catarina

AU - Whitney, Kristen

AU - Bertucci, Taylor

AU - Berlind, Joshua E.

AU - Lai, Jesse D.

AU - Garza, Jacob C.

AU - Boles, Nathan C.

AU - Mahali, Sidhartha

AU - Strang, Kevin H.

AU - Marsh, Jacob A.

AU - Chen, Cynthia

AU - Pugh, Derian A.

AU - Liu, Yiyuan

AU - Gordon, Ronald E.

AU - Goderie, Susan K.

AU - Chowdhury, Rebecca

AU - Lotz, Steven

AU - Lane, Keith

AU - Crary, John F.

AU - Haggarty, Stephen J.

AU - Karch, Celeste M.

AU - Ichida, Justin K.

AU - Goate, Alison M.

AU - Temple, Sally

N1 - Funding Information: We are grateful to the Tau Consortium and Rainwater Charitable Foundation for supporting this project, CurePSP for protocol development support, and the New York Genome Center for scRNA-seq expertise. We thank the research subjects and their families for their generous participation, including in ARTFL (U54NS092089) and LEFFTDS (U01AG045390), and support staff at participating sites. We thank Shawn Sutton, Brian Unruh, Isabel Tian, Khadijah Onanuga, and Nicholas St. John at the NeuraCell core facility (https://www.neuracell.org/) for organoid production; the ISMMS Neuropathology Brain Bank & Research Core for technical assistance and Aaron Bell for sample preparation; and the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine for equipment access. Elements of Figures 1A and 2B and the graphical abstract were created with BioRender. This work was supported by the Tau Consortium; the Rainwater Charitable Foundation (to C.M.K. J.F.C. S.J.H. J.K.I. A.M.G. and S.T.); NIH AG046374 (to C.M.K.); CurePSP (to K.R.B.); the MGH Research Scholars Program (to S.J.H.); the Association for Frontotemporal Degeneration (AFTD; to M.C.S. and K.R.B.); the BrightFocus Foundation (to K.R.B.); the Farrell Family Alzheimer's Disease Research Fund; NIH NS110890 (to C.M.K.); NIH R01AG054008 and R01NS095252 (to J.F.C.); NIH/NINDS R35 NS097277 (to S.T.); NIH/NIA R01 AG056293 (to S.T. and C.M.K.); NIH 2R01NS097850; Department of Defense W81XWH-21-1-0168, W81XWH-20-1-0424, and W81XWH-21-1-0131; the Harrington Discovery Institute; CIRM, the ALS Association; the John Douglas French Alzheimer's Foundation; ADDF, the New York Stem Cell Foundation (to J.K.I.); an Amgen postdoctoral fellowship (to J.D.L.); and NIH NINDS/NIA F31NS117075 (to J.E.B.). Neuracell received support from the Empire State Stem Cell Fund (NYSTEM) through New York State Department of Health contract C029158. Opinions expressed here are solely those of the authors and do not necessarily reflect those of the Empire State Stem Cell Board, the New York State Department of Health, or the State of New York. Conceptualization, K.R.B. M.C.S. J.C.G. C.M.K. J.K.I. S.J.H. J.F.C. A.M.G. and S.T.; methodology, K.R.B. M.C.S. J.C.G. K.H.S. K.W. S.K.G. S.L. K.L. J.K.I. S.M. J.F.C. C.M.K. D.A.P. N.C.B. T.B. and R.C.; software, K.R.B. K.W. and N.C.B.; formal analysis, K.R.B. K.W. T.B. J.C.G. J.E.B. J.D.L. J.K.I. S.M. C.M.K. Y.L. N.C.B. R.E.G. and S.K.G.; investigation, K.R.B. M.C.S. T.B. J.C.G. K.H.S. K.W. S.M. J.A.M. C.C. J.E.B. J.D.L. and R.C.; resources, K.W. S.K.G. J.E.B. J.D.L. S.L. J.K.I. C.M.K. and S.T.; data curation, K.R.B. K.W. and T.B.; writing – original draft, K.R.B. M.C.S. and T.B.; writing – review & editing, K.R.B. M.C.S. C.M.K. J.K.I. S.J.H. J.F.C. A.M.G. S.T. K.W. S.M. and R.C.; supervision, C.M.K. J.K.I. S.J.H. J.F.C. A.M.G. and S.T.; project administration, S.K.G. S.L. A.M.G. T.B. and S.T.; funding acquisition, K.R.B. M.C.S. C.M.K. J.K.I. S.J.H. A.M.G. and S.T. J.D.L. employee, Amgen. A.M.G.: Scientific Advisory Board (SAB), Denali Therapeutics (2015–2018); Genetic SAB, Pfizer (2019); SAB, Genentech; consultant, GSK, AbbVie, Biogen, and Eisai. S.J.H.: SAB, Rodin Therapeutics, Frequency Therapeutics, Psy Therapeutics, Vesigen Therapeutics, and Souvien Therapeutics; inventor, patent 6,475,723. S.T.: president, StemCultures; cofounder, LUXA Biotech; SAB, Sana Biotechnology, Blue Rock Therapeutics, and Vita Therapeutics; inventor, patent 16/331,063. J.K.I.: cofounder, AcuraStem and Modulo Bio; SAB, Spinogenix. Named companies were not involved in this project. Funding Information: We are grateful to the Tau Consortium and Rainwater Charitable Foundation for supporting this project, CurePSP for protocol development support, and the New York Genome Center for scRNA-seq expertise. We thank the research subjects and their families for their generous participation, including in ARTFL ( U54NS092089 ) and LEFFTDS ( U01AG045390 ), and support staff at participating sites. We thank Shawn Sutton, Brian Unruh, Isabel Tian, Khadijah Onanuga, and Nicholas St. John at the NeuraCell core facility ( https://www.neuracell.org/ ) for organoid production; the ISMMS Neuropathology Brain Bank & Research Core for technical assistance and Aaron Bell for sample preparation; and the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine for equipment access. Elements of Figures 1 A and 2 B and the graphical abstract were created with BioRender. This work was supported by the Tau Consortium ; the Rainwater Charitable Foundation (to C.M.K., J.F.C., S.J.H., J.K.I., A.M.G., and S.T.); NIH AG046374 (to C.M.K.); CurePSP (to K.R.B.); the MGH Research Scholars Program (to S.J.H.); the Association for Frontotemporal Degeneration (AFTD; to M.C.S. and K.R.B.); the BrightFocus Foundation (to K.R.B.); the Farrell Family Alzheimer’s Disease Research Fund ; NIH NS110890 (to C.M.K.); NIH R01AG054008 and R01NS095252 (to J.F.C.); NIH /NINDS R35 NS097277 (to S.T.); NIH /NIA R01 AG056293 (to S.T. and C.M.K.); NIH 2R01NS097850 ; Department of Defense W81XWH-21-1-0168 , W81XWH-20-1-0424 , and W81XWH-21-1-0131 ; the Harrington Discovery Institute ; CIRM , the ALS Association ; the John Douglas French Alzheimer’s Foundation ; ADDF , the New York Stem Cell Foundation (to J.K.I.); an Amgen postdoctoral fellowship (to J.D.L.); and NIH NINDS /NIA F31NS117075 (to J.E.B.). Neuracell received support from the Empire State Stem Cell Fund (NYSTEM) through New York State Department of Health contract C029158 . Opinions expressed here are solely those of the authors and do not necessarily reflect those of the Empire State Stem Cell Board, the New York State Department of Health, or the State of New York. Publisher Copyright: © 2021

PY - 2021/8/19

Y1 - 2021/8/19

N2 - 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.

AB - 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.

KW - ELAVL4

KW - MAPT

KW - autophagy

KW - frontotemporal dementia

KW - glutamatergic neurons

KW - organoids

KW - splicing

KW - synaptic signaling

KW - tauopathy

UR - http://www.scopus.com/inward/record.url?scp=85112749319&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.07.003

DO - 10.1016/j.cell.2021.07.003

M3 - Article

C2 - 34314701

AN - SCOPUS:85112749319

SN - 0092-8674

VL - 184

SP - 4547-4563.e17

JO - Cell

JF - Cell

IS - 17

ER -

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

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