Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation.

Chiara Urbinati,Giovanni Laviola,Carla Fiorentini,Bianca De Filippis,Daniele Vigli,Elena Angela Pia Germinario,Livia Cosentino,Alessia Fabbri,Daniela Valenti,Laura Ricceri,Rosa Anna Vacca

doi:10.3390/ijms22136739

Abstract

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models.

Highlights

Rett syndrome (RTT; OMIM #312750) is an early-onset neurologic disorder that manifests in a wide range of symptom severities [1]
We have reported that a single intracerebroventricular injection of a bacterial toxin, named cytotoxic necrotising factor 1 (CNF1), persistently rescues cognitive and motor impairments, and synaptic plasticity deficits in a RTT mouse model carrying a MeCP2 late truncating mutation that reproduces the condition of milder RTT cases (MeCP2-308 mice) [10]
Given the heterogeneity of methylCpG-binding protein 2 (MECP2) mutations in RTT patients, to test the robustness and generalisation of CNF1 therapeutic efficacy, the present study extended the investigation to a second RTT mouse model, characterised by a more severe phenotype, carrying a MeCP2 null mutation modelling the large deletions found in 10% of RTT patients (MeCP2Bird mice) [18]

Summary

Introduction

Rett syndrome (RTT; OMIM #312750) is an early-onset neurologic disorder that manifests in a wide range of symptom severities [1]. RTT is classified as a rare X-linked dominant disorder affecting mostly females (1 in 10,000 female births), since males are more severely affected, and rarely survive infancy [2]. In its classical form, RTT patients show an apparently normal psychomotor development until 6–18 months of age, when a characteristic neurological regression occurs, with loss of acquired motor, communicative, and cognitive skills, and development of autistic-like features [1]. Most classic RTT cases are caused by de novo mutations in the X-linked gene methylCpG-binding protein 2 (MECP2) [1]. The molecular mechanisms leading from MECP2 gene mutations to RTT symptomatology and progression have not been completely clarified. No effective therapy is currently available [5]

Methods

Results

Conclusion