Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants

Area of Science:

• Neuroscience
• Genetics
• Metabolic Disorders

Background:

• Monogenic neurodevelopmental disorders involve broadly expressed genes, suggesting systemic disease.
• Rett syndrome, caused by MECP2 mutations, serves as a model for investigating these systemic impacts.

Purpose of the Study:

• To test the systemic disease model in Rett syndrome.
• To investigate the impact of Mecp2/MECP2 mutations on transcriptomes and proteomes across various tissues and cell types.

Main Methods:

• Analysis of transcriptomes and proteomes in Mecp2-null mice (organs and brain regions).
• Assessment of diverse MECP2-null human cell lines (male and female).
• Bioinformatic analysis of gene product annotations, focusing on synaptic and metabolic pathways.

Main Results:

• Widespread transcriptome and proteome changes were observed in presymptomatic Mecp2-null mice and mutant human cells.
• Modifications were consistent across cortex, liver, kidney, and skeletal muscle, with notable impacts on synaptic and metabolic pathways.
• MECP2 mutations impaired pyruvate-dependent mitochondrial respiration but preserved glutamine utilization.

Conclusions:

• Mecp2/MECP2 mutations trigger systemic perturbations in lipid and mitochondrial metabolism.
• These mutations reduce cellular flexibility in utilizing mitochondrial fuels, contributing to neurodevelopmental impacts.
• Rett syndrome exemplifies a systemic disease with broad metabolic consequences beyond the central nervous system.