Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models.

Autor:	Esposito A; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. esposito.alessandro@hsr.it., Seri T; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Breccia M; Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate, Italy., Indrigo M; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., De Rocco G; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate, Italy., Nuzzolillo F; Vita-Salute San Raffaele University, Milan, Italy., Denti V; School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy., Pappacena F; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Tartaglione G; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Serrao S; School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy., Paglia G; School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy., Murru L; CNR Institute of Neuroscience, Vedano al Lambro, Italy., de Pretis S; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy., Cioni JM; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Landsberger N; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate, Italy., Guarnieri FC; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. fabrizia.guarnieri@in.cnr.it.; CNR Institute of Neuroscience, Vedano al Lambro, Italy. fabrizia.guarnieri@in.cnr.it., Palmieri M; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. palmieri.michela@hsr.it.; Vita-Salute San Raffaele University, Milan, Italy. palmieri.michela@hsr.it.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Nov; Vol. 16 (11), pp. 2795-2826. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1038/s44321-024-00151-w
Abstrakt:	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. Competing Interests: Disclosure and competing interests statement The authors declare no competing interests. (© 2024. The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu