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Molecular Research on Rett Syndrome and Related Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (25 November 2021) | Viewed by 16289

Special Issue Editor


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Guest Editor
1. Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
2. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Interests: Rett syndrome; epilepsy; BDNF; neurotrophins; adenosine
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Special Issue Information

Dear Colleagues,

Rett Syndrome (RTT) is a serious lifelong neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2; OMI#300005). However, many atypical cases of Rett syndrome have been associated with mutations in other genes, such as the X-linked cyclin-dependent kinase-like 5 (CDKL5; OMIM #300203) or the Forkhead box G1 (FOXG1; OMIM #164874). In addition, in recent years, more genes have been related to the RTT-like phenotype, and some of these genes have also been identified as causative for atypical RTT or RTT-like phenotype in the patients.

To date, there has been a lack of therapeutic strategies to help these patients, and it is crucial to shed light on the many unknown aspects of these disorders. Therefore, this Special Issue provides a forum for the publication of top-quality research papers on molecular and cellular mechanisms underlying Rett syndrome and related disorders, the neural systems and underpinning behavioral-associated features and findings relevant to the development of new therapies.

Dr. Maria J. Diogenes
Guest Editor

Manuscript Submission Information

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Keywords

  • Rett syndrome
  • atypical Rett
  • epileptic encephalopathies
  • neurodelopmental disorders
  • MECP2
  • FOXG1
  • CDKL5

Published Papers (4 papers)

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Research

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20 pages, 3412 KiB  
Article
WGCNA Identifies Translational and Proteasome-Ubiquitin Dysfunction in Rett Syndrome
by Florencia Haase, Brian S. Gloss, Patrick P. L. Tam and Wendy A. Gold
Int. J. Mol. Sci. 2021, 22(18), 9954; https://doi.org/10.3390/ijms22189954 - 15 Sep 2021
Cited by 8 | Viewed by 3324
Abstract
Rett Syndrome (RTT) is an X linked neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in severe cognitive and physical disabilities. Despite an apparent normal prenatal and postnatal development period, symptoms usually present around 6 to [...] Read more.
Rett Syndrome (RTT) is an X linked neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in severe cognitive and physical disabilities. Despite an apparent normal prenatal and postnatal development period, symptoms usually present around 6 to 18 months of age. Little is known about the consequences of MeCP2 deficiency at a molecular and cellular level before the onset of symptoms in neural cells, and subtle changes at this highly sensitive developmental stage may begin earlier than symptomatic manifestation. Recent transcriptomic studies of patient induced pluripotent stem cells (iPSC)-differentiated neurons and brain organoids harbouring pathogenic mutations in MECP2, have unravelled new insights into the cellular and molecular changes caused by these mutations. Here we interrogated transcriptomic modifications in RTT patients using publicly available RNA-sequencing datasets of patient iPSCs harbouring pathogenic mutations and healthy control iPSCs by Weighted Gene Correlation Network Analysis (WGCNA). Preservation analysis identified core gene pathways involved in translation, ribosomal function, and ubiquitination perturbed in some MECP2 mutant iPSC lines. Furthermore, differential gene expression of the parental fibroblasts and iPSC-derived neurons revealed alterations in genes in the ubiquitination pathway and neurotransmission in fibroblasts and differentiated neurons respectively. These findings might suggest that global translational dysregulation and proteasome ubiquitin function in Rett syndrome begins in progenitor cells prior to lineage commitment and differentiation into neural cells. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders)
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16 pages, 1554 KiB  
Article
Analysis of Astroglial Secretomic Profile in the Mecp2-Deficient Male Mouse Model of Rett Syndrome
by Yann Ehinger, Valerie Matagne, Valérie Cunin, Emilie Borloz, Michel Seve, Sandrine Bourgoin-Voillard, Ana Borges-Correia, Laurent Villard and Jean-Christophe Roux
Int. J. Mol. Sci. 2021, 22(9), 4316; https://doi.org/10.3390/ijms22094316 - 21 Apr 2021
Cited by 5 | Viewed by 3190
Abstract
Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of [...] Read more.
Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of MECP2 in astrocytes to the appearance and progression of the RTT phenotype in a non-cell autonomous manner and mechanisms are still unknown. Here, we used primary astroglial cells from Mecp2-deficient (KO) pups to identify deregulated secreted proteins. Using a differential quantitative proteomic analysis, twenty-nine proteins have been identified and four were confirmed by Western blotting with new samples as significantly deregulated. To further verify the functional relevance of these proteins in RTT, we tested their effects on the dendritic morphology of primary cortical neurons from Mecp2 KO mice that are known to display shorter dendritic processes. Using Sholl analysis, we found that incubation with Lcn2 or Lgals3 for 48 h was able to significantly increase the dendritic arborization of Mecp2 KO neurons. To our knowledge, this study, through secretomic analysis, is the first to identify astroglial secreted proteins involved in the neuronal RTT phenotype in vitro, which could open new therapeutic avenues for the treatment of Rett syndrome. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders)
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Review

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16 pages, 1573 KiB  
Review
Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective
by Ipek Akol, Fabian Gather and Tanja Vogel
Int. J. Mol. Sci. 2022, 23(2), 954; https://doi.org/10.3390/ijms23020954 - 16 Jan 2022
Cited by 6 | Viewed by 3917
Abstract
Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning [...] Read more.
Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes, ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits, with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in the neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as the increased yield of information from high throughput omics, have opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of the clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems, to highlight the prospects of research and possible clinical interventions. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders)
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24 pages, 4110 KiB  
Review
Modeling Rett Syndrome with Human Pluripotent Stem Cells: Mechanistic Outcomes and Future Clinical Perspectives
by Ana Rita Gomes, Tiago G. Fernandes, Joaquim M.S. Cabral and Maria Margarida Diogo
Int. J. Mol. Sci. 2021, 22(7), 3751; https://doi.org/10.3390/ijms22073751 - 03 Apr 2021
Cited by 11 | Viewed by 4919
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Among many different roles, MeCP2 has a high phenotypic impact during the different stages of brain development. Thus, it is essential to intensively investigate [...] Read more.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Among many different roles, MeCP2 has a high phenotypic impact during the different stages of brain development. Thus, it is essential to intensively investigate the function of MeCP2, and its regulated targets, to better understand the mechanisms of the disease and inspire the development of possible therapeutic strategies. Several animal models have greatly contributed to these studies, but more recently human pluripotent stem cells (hPSCs) have been providing a promising alternative for the study of RTT. The rapid evolution in the field of hPSC culture allowed first the development of 2D-based neuronal differentiation protocols, and more recently the generation of 3D human brain organoid models, a more complex approach that better recapitulates human neurodevelopment in vitro. Modeling RTT using these culture platforms, either with patient-specific human induced pluripotent stem cells (hiPSCs) or genetically-modified hPSCs, has certainly contributed to a better understanding of the onset of RTT and the disease phenotype, ultimately allowing the development of high throughput drugs screening tests for potential clinical translation. In this review, we first provide a brief summary of the main neurological features of RTT and the impact of MeCP2 mutations in the neuropathophysiology of this disease. Then, we provide a thorough revision of the more recent advances and future prospects of RTT modeling with human neural cells derived from hPSCs, obtained using both 2D and organoids culture systems, and its contribution for the current and future clinical trials for RTT. Full article
(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders)
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