Reduced expression of<i>MECP2</i>affects cell commitment and maintenance in neurons by triggering senescence: new perspective for Rett syndrome

Squillaro, Tiziana; Alessio, Nicola; Cipollaro, Marilena; Melone, Mariarosa Anna Beatrice; Hayek, Joussef; Renieri, Alessandra; Giordano, Antonio; Galderisi, Umberto

doi:10.1091/mbc.e11-09-0784

Cited by 39 publications

(34 citation statements)

References 37 publications

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“…Previous research studies on MeCP2 have shown that both deficiency (Nagarajan et al 2006;Squillaro et al 2012;Smrt et al 2007) and overexpression (Bodda et al 2013;Na et al 2012;Collins et al 2004) of MeCP2 lead to severe neurological complications. However, expression and function of MeCP2 in neurodevelopmental disorders are the focus of most MeCP2-related research work.…”

Section: Regulatory Mechanisms Of Mecp2 In Brainmentioning

confidence: 99%

Rett Syndrome and MeCP2

2014

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Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

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Section: Regulatory Mechanisms Of Mecp2 In Brainmentioning

confidence: 99%

Rett Syndrome and MeCP2

2014

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“…In addition to stress-induced senescence, there is also evidence for CS in neuroblastoma cells as a result of altered gene expression. Knockdown of MECP2, a chromatin-modifying protein that mediates gene silencing increases β-gal staining in a neuroblastoma cell line (Squillaro et al, 2012). In neurons, MECP2 mediates the expression of immediate early gene expression, a set of genes important for synaptic plasticity and memory formation (Deng et al, 2014).…”

Section: Senescence In the Cnsmentioning

confidence: 99%

Are there roles for brain cell senescence in aging and neurodegenerative disorders?

et al. 2014

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The term cellular senescence was introduced more than five decades ago to describe the state of growth arrest observed in aging cells. Since this initial discovery, the phenotypes associated with cellular senescence have expanded beyond growth arrest to include alterations in cellular metabolism, secreted cytokines, epigenetic regulation and protein expression. Recently, senescence has been shown to play an important role in vivo not only in relation to aging, but also during embryonic development. Thus, cellular senescence serves different purposes and comprises a wide range of distinct phenotypes across multiple cell types. Whether all cell types, including post-mitotic neurons, are capable of entering into a senescent state remains unclear. In this review we examine recent data that suggest that cellular senescence plays a role in brain aging and, notably, may not be limited to glia but also neurons. We suggest that there is a high level of similarity between some of the pathological changes that occur in the brain in Alzheimer’s and Parkinson’s diseases and those phenotypes observed in cellular senescence, leading us to propose that neurons and glia can exhibit hallmarks of senescence previously documented in peripheral tissues.

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“…This approach allows more accessible cell types, such as dermal fibroblasts from a skin biopsy or lymphocytes in peripheral blood, to be reprogrammed to pluripotent cells. Using this technique, which relies on the expression of cocktails of transcription factors, such as OCT4, SOX2, KLF4 , and c-MYC (10, 12), or OCT4, SOX2, NANOG , and LIN28 (11), there now exist a growing number of human iPSCs models of monogenic psychiatric disorders such as Fragile X syndrome (13–15), Rett syndrome (16–22), along with smaller number of examples of complex, polygenic psychiatric disorders, including schizophrenia (23–26), and bipolar disorder (27). …”

Section: Introductionmentioning

confidence: 99%

Translation: Screening for Novel Therapeutics With Disease-Relevant Cell Types Derived from Human Stem Cell Models

Haggarty

Perlis

2014

Biological Psychiatry

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The advent of somatic cell reprogramming technologies, which enables the generation of patient-specific, induced pluripotent stem cell (iPSC) and other trans-differentiated human neuronal cell models, provides new means of gaining insight into the molecular mechanisms and neural substrates of psychiatric disorders. By allowing a more precise understanding of genotype-phenotype relationship in disease-relevant human cell types, the use of reprogramming technologies in tandem with emerging genome engineering approaches provides a previously ‘missing link’ between basic research and translational efforts. In this review, we summarize advances in applying human pluripotent stem cell and reprogramming technologies to generate specific neural subtypes with a focus on the use of these in vitro systems for the discovery of small molecule-probes and novel therapeutics. Examples are given where human cell models of psychiatric disorders have begun to reveal new mechanistic insight into pathophysiology and simultaneously have provided the foundation for developing disease-relevant, phenotypic assays suitable for both functional genomic and chemical screens. A number of areas for future research are discussed, including the need to develop robust methodology for the reproducible, large-scale production of disease-relevant, neural cell types in formats compatible with high-throughput screening modalities, including high-content imaging, multidimensional, signature-based screening, and in vitro network using multielectrode arrays. Limitations, including the challenges in recapitulating neurocircuits and non-cell autonomous phenotypes are discussed. While these technologies are still in active development, we conclude that as our understanding of how to efficiently generate and probe the plasticity of patient-specific stem models improves, their utility is likely to advance rapidly.

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Reduced expression ofMECP2affects cell commitment and maintenance in neurons by triggering senescence: new perspective for Rett syndrome

Cited by 39 publications

References 37 publications

Rett Syndrome and MeCP2

Rett Syndrome and MeCP2

Are there roles for brain cell senescence in aging and neurodegenerative disorders?

Translation: Screening for Novel Therapeutics With Disease-Relevant Cell Types Derived from Human Stem Cell Models

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