Defects in Autophagy are Implicated in a Mecp2-mutant Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a rare neuro-metabolic disorder, with most cases caused by de novo mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Although several metabolic pathways have been implicated in RTT pathology, much of the underlying biology behind the disorder remains unknown. Interestingly, perturbations in the autophagy pathway, which has not been well studied in RTT, are consistent with many of the metabolic features of RTT pathogenesis. I found multiple lines of evidence for impaired autophagy in Mecp2-mutant mice, in vivo and in mouse embryonic fibroblasts. Systemically, autophagy is elevated prior to outward metabolic phenotypes, but is defective following aberrant lipid accumulation. Together, these results show that autophagy is abnormal in Mecp2-mutant mice and suggest that certain autophagic cargo are affected more than others. My findings highlight the similarities RTT has to other neurological and metabolic disorders with autophagic defects, providing exciting new insight.M.Sc