{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bowles KR"],"funding":["NIA NIH HHS","NINDS NIH HHS","NIH HHS"],"pagination":["4547-4563.e17"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8635409"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["184(17)"],"pubmed_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."],"journal":["Cell"],"pubmed_title":["ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids."],"pmcid":["PMC8635409"],"funding_grant_id":["R56 NS110890","S10 OD026880","U54 NS092089","P50 AG005681","R35 NS097277","R01 AG054008","F31 NS117075","RF1 NS110890","P30 AG066444","R01 AG056293","U01 AG045390","K01 AG046374","R01 NS097850","R01 NS095252"],"pubmed_authors":["Garza JC","Berlind JE","Bowles KR","Chowdhury R","Gordon RE","Lane K","Haggarty SJ","Lai JD","Liu Y","Silva MC","Ichida JK","Karch CM","Boles NC","Goate AM","Bertucci T","Lotz S","Goderie SK","Pugh DA","Mahali S","Marsh JA","Whitney K","Chen C","Temple S","Strang KH","Crary JF"],"additional_accession":[]},"is_claimable":false,"name":"ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.","description":"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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Aug","modification":"2024-11-09T05:29:38.934Z","creation":"2024-11-09T05:29:38.934Z"},"accession":"S-EPMC8635409","cross_references":{"pubmed":["34314701"],"doi":["10.1016/j.cell.2021.07.003"]}}