Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Biology

Background:

• Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurodevelopmental disorder characterized by synaptic deficits and metabolic dysfunction.
• Autophagy, a cellular degradation process, is crucial for neuronal homeostasis, but its role in RTT neuropathogenesis is not well understood.

Purpose of the Study:

• To investigate the autophagic pathway's involvement in Rett syndrome.
• To explore the therapeutic potential of modulating autophagy in RTT models.

Main Methods:

• Examined autophagic vacuoles and LC3B lipidation in Mecp2 knock-out (KO) neurons.
• Administered trehalose, an autophagy inducer, to Mecp2 KO neurons and mice.
• Assessed neuronal morphology, activity, synaptic ultrastructure, and motor behavior.

Main Results:

• Mecp2 KO neurons exhibited reduced autophagic vacuoles and defective LC3B lipidation, suggesting impaired autophagosome formation.
• Trehalose treatment restored LC3B lipidation and autophagosome content, improving neuronal morphology, activity, and synaptic structure in vitro.
• Trehalose administration ameliorated motor and exploratory deficits in Mecp2 KO mice.

Conclusions:

• Autophagy is impaired in RTT models, contributing to neuropathogenesis.
• Trehalose-induced autophagy modulation represents a promising therapeutic strategy for Rett syndrome and potentially other neurodevelopmental disorders.