Human iPSC-derived neurons reveal early developmental alteration of neurite outgrowth in the late-occurring neurodegenerative Wolfram syndrome.
Am J Hum Genet
; 108(11): 2171-2185, 2021 11 04.
Article
em En
| MEDLINE
| ID: mdl-34699745
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Wolfram
/
Neuritos
/
Idade de Início
/
Células-Tronco Pluripotentes Induzidas
/
Neurônios
Tipo de estudo:
Guideline
/
Observational_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
França