ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.
Autophagy
/ drug effects
Biomarkers
/ metabolism
Body Patterning
/ drug effects
Cell Death
/ drug effects
Cell Line
Cerebrum
/ pathology
ELAV-Like Protein 4
/ genetics
Glutamic Acid
/ metabolism
Humans
Hydrazones
/ pharmacology
Lysosomes
/ drug effects
Morpholines
/ pharmacology
Mutation
/ genetics
Neurons
/ drug effects
Organoids
/ drug effects
Phosphorylation
/ drug effects
Pyrimidines
/ pharmacology
RNA Splicing
/ drug effects
Signal Transduction
/ drug effects
Stress Granules
/ drug effects
Synapses
/ metabolism
Up-Regulation
/ drug effects
tau Proteins
/ genetics
ELAVL4
MAPT
autophagy
frontotemporal dementia
glutamatergic neurons
organoids
splicing
synaptic signaling
tauopathy
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
19 08 2021
19 08 2021
Historique:
received:
23
01
2021
revised:
06
05
2021
accepted:
30
06
2021
pubmed:
28
7
2021
medline:
6
1
2022
entrez:
27
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34314701
pii: S0092-8674(21)00829-1
doi: 10.1016/j.cell.2021.07.003
pmc: PMC8635409
mid: NIHMS1753168
pii:
doi:
Substances chimiques
Biomarkers
0
ELAV-Like Protein 4
0
Hydrazones
0
MAPT protein, human
0
Morpholines
0
Pyrimidines
0
tau Proteins
0
Glutamic Acid
3KX376GY7L
apilimod
GFW2K84S4L
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4547-4563.e17Subventions
Organisme : NIA NIH HHS
ID : P30 AG066444
Pays : United States
Organisme : NINDS NIH HHS
ID : F31 NS117075
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG005681
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097277
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS110890
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS110890
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests 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.
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