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 journalArticlepeer-review

16 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 languageEnglish
Pages (from-to)4547-4563.e17
JournalCell
Volume184
Issue number17
DOIs
StatePublished - Aug 19 2021

Keywords

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

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