Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2024-10-14
DOI
https://doi.org/10.1038/s44321-024-00151-w
Citations
6
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
3.30

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article

Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models

Michela Palmieri, Giuseppe Paglia, Luca Murru, Stefano de Pretis et al.
6 citations
EMBO Molecular Medicine
Genetics and Neurodevelopmental Disorders
3.30
article

Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models

Michela Palmieri, Giuseppe Paglia, Luca Murru, Stefano de Pretis, Giuseppina De Rocco, Nicoletta Landsberger, Alessandro Esposito, Marzia Indrigo, Jean-Michel Cioni, Francesca Nuzzolillo, Gaia Tartaglione, Fabrizia Claudia Guarnieri, Simone Serrao, Tommaso Seri, Vanna Denti, Martina Breccia, Francesca Pappacena
article en
6 citations

Abstract

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.

EMBO Molecular MedicineVol. 16(11)
Vita-Salute San Raffaele University (IT), University of Milan (IT), San Raffaele University of Rome (IT), Neuroscience Institute (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Institute of Biomedical Technologies (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), University of Milano-Bicocca (IT)
Ministero della Salute
Good health and well-being
Openalex Percentile: Top 8%
Genetics and Neurodevelopmental Disorders
3.30
DOIOpen Access PDFOpenAlex
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