MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome.

Derek J C Tai,Yun L Ma,Wei L Hsu,Eminy H Y Lee,Sin J Cheng,Shau Y Liu,Yen C Liu

doi:10.1038/ncomms10552

Abstract

The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). However, the molecular mechanism of MECP2-mutation-caused RTT is less known. Here we find that MeCP2 could be SUMO-modified by the E3 ligase PIAS1 at Lys-412. MeCP2 phosphorylation (at Ser-421 and Thr-308) facilitates MeCP2 SUMOylation, and MeCP2 SUMOylation is induced by NMDA, IGF-1 and CRF in the rat brain. MeCP2 SUMOylation releases CREB from the repressor complex and enhances Bdnf mRNA expression. Several MECP2 mutations identified in RTT patients show decreased MeCP2 SUMOylation. Re-expression of wild-type MeCP2 or SUMO-modified MeCP2 in Mecp2-null neurons rescues the deficits of social interaction, fear memory and LTP observed in Mecp2 conditional knockout (cKO) mice. These results together reveal an important role of MeCP2 SUMOylation in social interaction, memory and synaptic plasticity, and that abnormal MeCP2 SUMOylation is implicated in RTT.

Highlights

The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT)
Results revealed that MeCP2 SUMOylation was observed when E1, E2, protein inhibitor of activated STAT1 (PIAS1) and MeCP2 proteins were added; this effect was blocked by the addition of sentrin-specific protease 1 (SENP1), an enzyme that removes the sumo molecule from sumo-conjugated protein (Fig. 1a)
We have found that MeCP2 could be small ubiquitin-like modifier (SUMO)-modified by PIAS1 at Lys-412 and blockade of MeCP2 SUMOylation at this residue worsens behavioural deficits in Mecp[2] conditional knockout (cKO) mice resembling that of RTT patients

Summary

Introduction

The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). Re-expression of wild-type MeCP2 or SUMO-modified MeCP2 in Mecp2-null neurons rescues the deficits of social interaction, fear memory and LTP observed in Mecp[2] conditional knockout (cKO) mice. These results together reveal an important role of MeCP2 SUMOylation in social interaction, memory and synaptic plasticity, and that abnormal MeCP2 SUMOylation is implicated in RTT. MeCP2 plays an important role in several neurodevelopmental disorders, such as Rett syndrome (RTT)[1,6,7], which is an autism spectrum disorder caused by mutations of the MECP2 gene and 218 mutations have been identified that are linked to RTT8 Among these mutations, there are three more common mutations, T158M, R168X (where X stands for a premature stop codon) and R133C, which account for B13, 12 and 7% of total RTT patients, respectively[9]. Our results show that MeCP2 SUMOylation rescues the behavioural and synaptic deficits in Mecp[2] conditional knockout (cKO) mice

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