RETT Syndrome

Co-Investigator: Prof. Galderisi Umberto Dr. Squillaro Tiziana

Studies on the Rett Syndrome

Rett syndrome (RTT) is one of the most common genetic causes of mental retardation in young females.

Despite a large amount of data on the role of Mecp2 as the causative gene in RTT, several questions remain unanswered. In fact, it is difficult to reconcile the major neurological symptoms of RTT pathology with the widespread expression pattern of Mecp2 and its promiscuous binding to chromosomes. Because RTT is a neurodevelopmental disease, researches primarily focused with respect to neuronal functions. Consequently, more subtle deficiencies, unrelated to neural activities and/or the impairment of cell functions outside the nervous system, may have been overlooked.

MECP2 is a member of a family of proteins that preferentially bind to methylated CpGs and the DNA methylation is an epigenetic modification that occurs almost exclusively in the context of CpG dinucleotides. 

Taking into account both the observation that Mecp2-impaired function may affect several organs apart from neural systems and the role of Mecp2 as a global regulator of gene expression, we have studied the in vitro behaviour of mesenchymal stem cells (MSCs) obtained from RTT patients in comparison with cells from healthy donors. We have RTT patients' MSCs because they are progenitors of osteocytes, and it has been suggested that RTT patients' osteogenesis could be impaired. Moreover, MSCs play a key role in the homeostasis of many organs and tissues. We found that senescence phenomena affect the biology of MSCs obtained from RTT patients and from RTT mouse model. Currently, we are investigating in depth the role of Mecp2 in the senescence of MSCs and other stem cell types, such as neural stem cells and satellite muscle cells.

OUR Publications:

1: Squillaro T, Hayek G, Farina E, Cipollaro M, Renieri A, Galderisi U. A case report: bone marrow mesenchymal stem cells from a Rett syndrome patient are prone to senescence and show a lower degree of apoptosis. J Cell Biochem. 2008 Apr 15;103(6):1877-85. PubMed PMID: 18059018.

2: Squillaro T, Alessio N, Cipollaro M, Renieri A, Giordano A, Galderisi U. Partial silencing of methyl cytosine protein binding 2 (MECP2) in mesenchymal stem cells induces senescence with an increase in damaged DNA. FASEB J. 2010 May;24(5):1593-603. doi: 10.1096/fj.09-143057. Epub 2010 Jan 11. Erratum in: FASEB J. 2016 May;30(5):2064. PubMed PMID: 20065105.

3: Squillaro T, Alessio N, Cipollaro M, Melone MA, Hayek G, Renieri A, Giordano A, Galderisi U. Reduced expression of MECP2 affects cell commitment and maintenance in neurons by triggering senescence: new perspective for Rett syndrome. Mol Biol Cell. 2012 Apr;23(8):1435-45. doi: 10.1091/mbc.E11-09-0784. Epub 2012 Feb 22. PubMed PMID: 22357617; PubMed Central PMCID: PMC3327309.

4: Alessio N, Riccitiello F, Squillaro T, Capasso S, Del Gaudio S, Di Bernardo G, Cipollaro M, Melone MAB, Peluso G, Galderisi U. Neural stem cells from a mouse model of Rett syndrome are prone to senescence, show reduced capacity to cope with genotoxic stress, and are impaired in the differentiation process. Exp Mol Med. 2018 Mar 22;50(3):1. doi: 10.1038/s12276-017-0005-x. PubMed PMID: 29563495; PubMed Central PMCID: PMC6118406.