Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non-protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both −/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain-specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress.

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

“…Likewise, our recent work in RTT murine models suggests that the presence of systemic oxidative stress (OS) precedes the onset of clinical symptoms in RTT mouse model and can be rescued by MeCP2 gene reexpression in the brain of the null mice [9]. Therefore, clinical and experimental evidence supports the concept that oxidative damage plays a previously unrecognized key role in the pathogenesis of RTT/ MeCP2 deficiency.…”

“…Our study was performed in primary skin fibroblasts isolated from RTT patients because this biological setup constitutes one of the most reliable approaches to investigate molecular and cellular mechanisms in genetic and neurological disorders [29]. Our goal here was to extend our previous study in which oxidative stress was detected in several RTT models [8,9]. As is well known, increased oxidative stress leads to lipid peroxidation and consequent production of reactive aldehydes, among which HNE is one of the most significant physiologically.…”

Clinical and biological progress over 50 years in Rett syndrome

“…The fact that a wide variety of genes are affected suggests that there is not going to be a single pathogenic pathway that can act as a focus for all therapeutic interventions. Downstream, many cellular systems are disrupted, and indeed there have been reports of altered synaptic function and plasticity, 43,[96][97][98][99][100] reduced protein synthesis, 101 impaired mitochondrial function, 102 oxidative stress 103 and alterations in various signalling and homeostatic pathways such as the mTOR/AKT pathway 101 and energy and lipid metabolism. 54 Which of these is most important to the cellular dysfunction may be cell-type and state dependent.…”

FBXL5 Inactivation in Mouse Brain Induces Aberrant Proliferation of Neural Stem Progenitor Cells

“…7K). The amount of non-protein-bound iron has recently been shown to be increased in the brain of a rodent model of autism as well as in human patients (17,49). Whether mTOR signaling is in part responsible for iron overload pathophysiology warrants further investigation with the use of preclinical model systems (18,20).…”

“…Recent studies suggest that iron metabolism plays an integral role in the maintenance of brain homeostasis, with abnormal accumulation of iron in the brain having been found to underlie the pathogenesis of several neurodegenerative diseases as well as neuropsychiatric disorders at various developmental stages (17)(18)(19). Iron deposits have thus been found in the substantia nigra and globus pallidus of individuals with such conditions, whereas other brain regions such as the cortex and hippocampus amass both ferric and ferrous iron (20)(21)(22).…”