Human iPSC-derived neurons reveal early developmental alteration of neurite outgrowth in the late-occurring neurodegenerative Wolfram syndrome.
Wolfram syndrome
axon guidance
endoplasmic reticulum stress
induced pluripotent stem cells
neurite outgrowth
neurodegenerative disease
neurodevelopmental disease
neurons
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
04 11 2021
04 11 2021
Historique:
received:
20
05
2021
accepted:
30
09
2021
pubmed:
27
10
2021
medline:
23
11
2021
entrez:
26
10
2021
Statut:
ppublish
Résumé
Recent studies indicate that neurodegenerative processes that appear during childhood and adolescence in individuals with Wolfram syndrome (WS) occur in addition to early brain development alteration, which is clinically silent. Underlying pathological mechanisms are still unknown. We have used induced pluripotent stem cell-derived neural cells from individuals affected by WS in order to reveal their phenotypic and molecular correlates. We have observed that a subpopulation of Wolfram neurons displayed aberrant neurite outgrowth associated with altered expression of axon guidance genes. Selective inhibition of the ATF6α arm of the unfolded protein response prevented the altered phenotype, although acute endoplasmic reticulum stress response-which is activated in late Wolfram degenerative processes-was not detected. Among the drugs currently tried in individuals with WS, valproic acid was the one that prevented the pathological phenotypes. These results suggest that early defects in axon guidance may contribute to the loss of neurons in individuals with WS.
Identifiants
pubmed: 34699745
pii: S0002-9297(21)00355-4
doi: 10.1016/j.ajhg.2021.10.001
pmc: PMC8595949
pii:
doi:
Substances chimiques
Valproic Acid
614OI1Z5WI
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2171-2185Informations de copyright
Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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