Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
19 04 2023
19 04 2023
Historique:
received:
17
11
2021
accepted:
05
04
2023
medline:
21
4
2023
pubmed:
20
4
2023
entrez:
19
04
2023
Statut:
epublish
Résumé
Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.
Identifiants
pubmed: 37076591
doi: 10.1038/s42003-023-04813-2
pii: 10.1038/s42003-023-04813-2
pmc: PMC10115838
doi:
Substances chimiques
Glucosylceramidase
EC 3.2.1.45
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
431Informations de copyright
© 2023. The Author(s).
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