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MeCP2 in the regulation of neural activity: Rett syndrome pathophysiological perspectives.

ABSTRACT: Rett syndrome (RTT), an X-linked neurodevelopment disorder, occurs in approximately one out of 10,000 females. Individuals afflicted by RTT display a constellation of signs and symptoms, affecting nearly every organ system. Most striking are the neurological manifestations, including regression of language and motor skills, increased seizure activity, autonomic dysfunction, and aberrant regulation of breathing patterns. The majority of girls with RTT have mutations in the gene encoding for methyl-CpG binding protein 2 (MeCP2). Since the discovery of this genetic cause of RTT in 1999, there has been an accelerated pace of research seeking to understand the role of MeCP2 in the brain in the hope of developing a disease-modifying therapy for RTT. In this study, we review the clinical features of RTT and then explore the latest mechanistic studies in order to explain how a mutation in MeCP2 leads to these unique features. We cover in detail studies examining the role of MeCP2 in neuronal physiology, as well as recent evidence that implicates a key role for glia in the pathogenesis of RTT. In the past 20 years, these basic and clinical studies have yielded an extraordinary understanding of RTT; as such, we end this narrative review considering the translation of these studies into clinical trials for the treatment of RTT.

SUBMITTER: Cuddapah VA

PROVIDER: S-EPMC7337177 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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MeCP2 in the regulation of neural activity: Rett syndrome pathophysiological perspectives.

Cuddapah Vishnu Anand VA Sinifunanya Elvee Nwaobi EN Percy Alan K AK Olsen Michelle Lynne ML

Degenerative neurological and neuromuscular disease 20151014

Rett syndrome (RTT), an X-linked neurodevelopment disorder, occurs in approximately one out of 10,000 females. Individuals afflicted by RTT display a constellation of signs and symptoms, affecting nearly every organ system. Most striking are the neurological manifestations, including regression of language and motor skills, increased seizure activity, autonomic dysfunction, and aberrant regulation of breathing patterns. The majority of girls with RTT have mutations in the gene encoding for methy ...[more]

PMID: 32669918

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Project description:Dysfunctions of MeCP2 protein lead to various neurological disorders such as Rett syndrome and Autism. The exact functions of MeCP2 protein is still far from clear. At a molecular level, there exist contradictory data. MeCP2 protein is considered a single immunoreactive band around 75 kDa by western-blot analysis but several reports have revealed the existence of multiple MeCP2 immunoreactive bands above and below the level where MeCP2 is expected. MeCP2 immunoreactive bands have been interpreted in different ways. Some researchers suggest that multiple MeCP2 immunoreactive bands are unidentified proteins that cross-react with the MeCP2 antibody or degradation product of MeCP2, while others suggest that MeCP2 post-transcriptional processing generates multiple molecular forms linked to cell signaling, but so far they have not been properly analyzed in relation to Rett syndrome experimental models. The purpose of this study is to advance understanding of multiple MeCP2 immunoreactive bands in control neural cells and p.T158M MeCP2e1 mutant cells. We have generated stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Application of N- and C- terminal MeCP2 antibodies, and also, RFP antibody minimized concerns about nonspecific cross-reactivity, since they react with the same antigen at different epitopes. We report the existence of multiple MeCP2 immunoreactive bands in control cells, stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Also, MeCP2 immunoreactive bands differences were found between wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Slower migration phosphorylated band around 70kDa disappeared in p.T158M MeCP2e1-RFP mutant expressing cells. These data suggest that threonine 158 could represent an important phosphorylation site potentially involved in protein function. Our results clearly indicate that MeCP2 antibodies have no cross-reactivity with similar epitopes on others proteins, supporting the idea that MeCP2 may exist in multiple different molecular forms and that molecular pattern variations derived from altered post-transcriptional processing may underlay Rett syndrome physiophatology.

Dataset Information

MeCP2 in the regulation of neural activity: Rett syndrome pathophysiological perspectives.

Publications

MeCP2 in the regulation of neural activity: Rett syndrome pathophysiological perspectives.

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