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

• 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

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...