Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models.
Autophagy
MeCP2
Metabolism
Neurons
Rett Syndrome
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
14 Oct 2024
14 Oct 2024
Historique:
received:
22
12
2023
accepted:
27
09
2024
revised:
16
09
2024
medline:
15
10
2024
pubmed:
15
10
2024
entrez:
14
10
2024
Statut:
aheadofprint
Résumé
Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles.Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.
Identifiants
pubmed: 39402139
doi: 10.1038/s44321-024-00151-w
pii: 10.1038/s44321-024-00151-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministero della Salute (Italy Ministry of Health)
ID : GR2019-12371236
Informations de copyright
© 2024. The Author(s).
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