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

63 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 (US)
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 - Aug 19 2021
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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

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

@article{712496ce15c8447aa851bd04eec41a6d,

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 = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = aug,

day = "19",

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

language = "English (US)",

volume = "184",

pages = "4547--4563.e17",

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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

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

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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

Abstract

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ASJC Scopus subject areas

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