Mitochondrial Dysfunction in the Pathogenesis of Rett Syndrome: Implications for Mitochondria-Targeted Therapies.

Natalya Shulyakova,James H Eubanks,Linda R Mills,Ana C Andreazza

doi:10.3389/fncel.2017.00058

Abstract

First described over 50 years ago, Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations of the X-linked MECP2 gene. RTT affects predominantly females, and has a prevalence of roughly 1 in every 10,000 female births. Prior to the discovery that mutations of MECP2 are the leading cause of RTT, there were suggestions that RTT could be a mitochondrial disease. In fact, several reports documented altered mitochondrial structure, and deficiencies in mitochondrial enzyme activity in different cells or tissues derived from RTT patients. With the identification of MECP2 as the causal gene, interest largely shifted toward defining the normal function of MeCP2 in the brain, and how its absence affects the neurodevelopment and neurophysiology. Recently, though, interest in studying mitochondrial function in RTT has been reignited, at least in part due to observations suggesting systemic oxidative stress does play a contributing role in RTT pathogenesis. Here we review data relating to mitochondrial alterations at the structural and functional levels in RTT patients and model systems, and present a hypothesis for how the absence of MeCP2 could lead to altered mitochondrial function and elevated levels of cellular oxidative stress. Finally, we discuss the prospects for treating RTT using interventions that target specific aspects of mitochondrial dysfunction and/or oxidative stress.

Highlights

Mutations of the gene encoding methyl-CpG-binding-domain-containing-protein 2 (MECP2) are the underlying cause for the vast majority of people affected with typical Rett syndrome (RTT; OMIN #312750) (Amir et al, 1999), with mutations of the genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box g1 (FOXG1) causal for other less common RTT cases (Weaving et al, 2004; Ariani et al, 2008)
Considerable data show impaired mitochondrial function occurs in MeCP2-deficient cells, and mechanisms through which these functional alterations arise beginning to be identified
Studies to date indicate that the loss of MeCP2 function negatively affects the signaling efficiency of a host of intracellular signaling pathways, the communicative ability of neuronal populations, the excitability of neural networks, and the functional efficiency of mitochondria

Summary

Introduction

Mutations of the gene encoding methyl-CpG-binding-domain-containing-protein 2 (MECP2) are the underlying cause for the vast majority of people affected with typical Rett syndrome (RTT; OMIN #312750) (Amir et al, 1999), with mutations of the genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box g1 (FOXG1) causal for other less common RTT cases (Weaving et al, 2004; Ariani et al, 2008). Clear indices of abnormal mitochondrial structure and function have been observed in different cell types derived from both symptomatic MeCP2-deficient mice as well as RTT patients (Tables 1–3).

Results

Conclusion