New drug target for Rett syndrome

Harvard Stem Cell Institute (HSCI) researchers have identified a faulty signaling pathway that, when corrected, in mice ameliorates the symptoms of Rett syndrome, a devastating neurological condition. The findings could lead to the discovery of compounds or drugs that may benefit children affected by the disease,
Source: World Pharma News - Category: Pharmaceuticals Tags: Featured Research Research and Development Source Type: news

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AbstractMeCP2 is an X-linked gene; its mutation causes Rett Syndrome (RTT), a severe neurodevelopmental disability that affects mainly girls. Acting as a transcription factor, the MeCP2 protein is able to regulate several hormone-related genes, such as the thyroid hormones (TH), which are known to play an important role in the development of the central nervous system (CNS). Although only a few studies have associated RTT and TH, TH deficit can lead to neurological deregulation by triggering functional deficiencies during adulthood. Here, we used human-induced pluripotent stem cell (iPSC) to generate MeCP2-knockout neurona...
Source: Molecular Neurobiology - Category: Neurology Source Type: research
In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in RTT. Intensified mitochondrial O2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT. Introduction Rett syndrome (RTT) is a progressive neurodevelopmental disorder. It primarily affects females, who show the first obvious symptoms within 6–18 months after birth. Among the characteristics are a regression of mental ...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Publication date: 8 May 2018Source: Stem Cell Reports, Volume 10, Issue 5Author(s): Minori Ohashi, Elena Korsakova, Denise Allen, Peiyee Lee, Kai Fu, Benni S. Vargas, Jessica Cinkornpumin, Carlos Salas, Jenny C. Park, Igal Germanguz, Justin Langerman, Contantinos Chronis, Edward Kuoy, Stephen Tran, Xinshu Xiao, Matteo Pellegrini, Kathrin Plath, William E. LowrySummaryTo determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate di...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research
iPSC-derived neurons profiling reveals GABAergic circuit disruption and acetylated α-tubulin defect which improves after iHDAC6 treatment in Rett syndrome. Exp Cell Res. 2018 May 03;: Authors: Landucci E, Brindisi M, Bianciardi L, Catania LM, Daga S, Croci S, Frullanti E, Fallerini C, Butini S, Brogi S, Furini S, Melani R, Molinaro A, Lorenzetti FC, Imperatore V, Amabile S, Mariani J, Mari F, Ariani F, Pizzorusso T, Pinto AM, Vaccarino FM, Campiani G, Renieri A, Meloni I Abstract Mutations in MECP2 gene have been identified in more than 95% of patients with classic Rett syndrome, one of the most...
Source: Experimental Cell Research - Category: Cytology Authors: Tags: Exp Cell Res Source Type: research
Publication date: 8 June 2018 Source:Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 84, Part B Author(s): Katrin Linda, Carol Fiuza, Nael Nadif Kasri A major challenge in clinical genetics and medicine is represented by genetically and phenotypically highly diverse neurodevelopmental disorders, like for example intellectual disability and autism. Intellectual disability is characterized by substantial limitations in cognitive function and adaptive behaviour. At the cellular level, this is reflected by deficits in synaptic structure and plasticity and therefore has been coined as a synaptic disorder...
Source: Progress in Neuro Psychopharmacology and Biological Psychiatry - Category: Psychiatry Source Type: research
We report that spontaneous calcium activity is abnormal in RTT astrocytesin vitro,in situ, and invivo. Such abnormal calcium activity is mediated by calcium overload in the endoplasmic reticulum caused by abnormal store operated calcium entry, which is in part dependent on elevated expression of TRPC4. Furthermore, the abnormal calcium activity leads to excessive activation of extrasynaptic NMDA receptors (eNMDARs) on neighboring neurons and increased network excitability inMecp2 knockout mice. Finally, both the abnormal astrocytic calcium activity and the excessive activation of eNMDARs are caused byMecp2 deletion in astr...
Source: eLife - Category: Biomedical Science Tags: Developmental Biology and Stem Cells Source Type: research
AbstractRSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show thatRSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show thatRSRC1 is ubiquitously expressed, and that theRSRC1 mutation triggers nonsense-mediated mRNA decay of theRSRC1 transcript in patients ’ fibroblasts. Short hairpin RNA (shRNA)-mediated lentiviral silencing and ov...
Source: Brain - Category: Neurology Source Type: research
Abstract Therapeutic intervention is an important need in ameliorating the severe consequences of Rett Syndrome (RTT), a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein-2 (MeCP2). Following previously observed morphological defects in induced pluripotent stem cell (iPSC)-derived neurons obtained from female RTT patients, we hypothesized that transfection with the L1 cell adhesion molecule (L1) could contribute to normalizing a pathological male cell system bearing a nonsense mutation of MeCP2. We found a decreased expression of L1 in RTT iPSCs-derived neural precursor cell...
Source: Biochemical and Biophysical Research communications - Category: Biochemistry Authors: Tags: Biochem Biophys Res Commun Source Type: research
Publication date: 6 June 2017 Source:Stem Cell Reports, Volume 8, Issue 6 Author(s): Tetsuro Yasui, Naohiro Uezono, Hideyuki Nakashima, Hirofumi Noguchi, Taito Matsuda, Tomoko Noda-Andoh, Hideyuki Okano, Kinichi Nakashima Human neural precursor cells (hNPCs) derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulati...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research
Authors: Riemens RJM, Soares ES, Esteller M, Delgado-Morales R Abstract Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized mode...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
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