rett syndrome
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Rett syndrome, MECP2 and therapeutic strategies
The development of the iPS cell technology has revolutionized our ability to study development and diseases in defined in vitro cell culture systems. The talk will focus on Rett Syndrome and discuss two topics: (i) the use of gene editing as an approach to therapy and (ii) the role of MECP2 in gene expression (i) The mutation of the X-linked MECP2 gene is causative for the disease. In a female patient, every cell has a wt copy that is, however, in 50% of the cells located on the inactive X chromosome. We have used epigenetic gene editing tools to activate the wt MECP2 allele on the inactive X chromosome. (ii) MECP2 is thought to act as repressor of gene expression. I will present data which show that MECP2 binds to Pol II and acts as an activator for thousands of genes. The target genes are significantly enriched for Autism related genes. Our data challenge the established model of MECP2’s role in gene expression and suggest novel therapeutic approaches.
ALBA webinar series - Breaking down the ivory tower: Ep. 4 Maria José Diógenes
With this webinar series, the ALBA Disability & Accessibility Working Group aims to bring down the ivory tower of ableism among the brain research community, one extraordinary neuroscientist at a time. These webinars give a platform to scientists with disabilities across the globe and neuroscience disciplines, while reflecting on how to promote inclusive working environments and accessibility to research. For this 4th episode, Dr. Maria José Diógenes (iMM - ULisboa, PT) will talk about how her personal story changed her professional life: from the pharmacy to the laboratory bench and from ageing to Rett Syndrome.
X-linked mosaicism and behavioral heterogeneity in Rett syndrome
Networking—the key to success… especially in the brain
In our everyday lives, we form connections and build up social networks that allow us to function successfully as individuals and as a society. Our social networks tend to include well-connected individuals who link us to other groups of people that we might otherwise have limited access to. In addition, we are more likely to befriend individuals who a) live nearby and b) have mutual friends. Interestingly, neurons tend to do the same…until development is perturbed. Just like social networks, neuronal networks require highly connected hubs to elicit efficient communication at minimal cost (you can’t befriend everybody you meet, nor can every neuron wire with every other!). This talk will cover some of Alex’s work showing that microscopic (cellular scale) brain networks inferred from spontaneous activity show similar complex topology to that previously described in macroscopic human brain scans. The talk will also discuss what happens when neurodevelopment is disrupted in the case of a monogenic disorder called Rett Syndrome. This will include simulations of neuronal activity and the effects of manipulation of model parameters as well as what happens when we manipulate real developing networks using optogenetics. If functional development can be restored in atypical networks, this may have implications for treatment of neurodevelopmental disorders like Rett Syndrome.
Using Human Stem Cells to Uncover Genetic Epilepsy Mechanisms
Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an increasingly utilized approach for neurological disease modeling with patient-derived cells. Several groups, including ours, have applied the iPSC approach to model severe genetic developmental and epileptic encephalopathies (DEEs) with patient-derived cells. Although most studies to date involve 2-D cultures of patient-derived neurons, brain organoids are increasingly being employed to explore genetic DEE mechanisms. We are applying this approach to understand PMSE (Polyhydramnios, Megalencephaly and Symptomatic Epilepsy) syndrome, Rett Syndrome (in collaboration with Ben Novitch at UCLA) and Protocadherin-19 Clustering Epilepsy (PCE). I will describe our findings of robust structural phenotypes in PMSE and PCE patient-derived brain organoid models, as well as functional abnormalities identified in fusion organoid models of Rett syndrome. In addition to showing epilepsy-relevant phenotypes, both 2D and brain organoid cultures offer platforms to identify novel therapies. We will also discuss challenges and recent advances in the brain organoid field, including a new single rosette brain organoid model that we have developed. The field is advancing rapidly and our findings suggest that brain organoid approaches offers great promise for modeling genetic neurodevelopmental epilepsies and identifying precision therapies.
Cannabidivarin and Neural Stem cells, a new hope for Rett Syndrome?
Buffering of transcription rate by mRNA half decay mechanisms is a conserved feature of Rett syndrome models
Disrupted interareal cortical dynamics and sensorimotor learning in a mouse model of Rett syndrome
Characterization of de novo GABAB2 variants linked to Rett Syndrome and Encephalopathic Epilepsy
Development of a new drug screening system for Rett syndrome therapy
Contribution of the adipocyte hormone leptin in the pathogenesis of Rett syndrome
Mitochondrial morphology and dynamic abnormalities in an in vitro model of Rett syndrome
Mitochondrial dysfunction in Rett syndrome mice models: studying a neurological disorder from synaptic metabolism perspective to find new treatment options
Reversal of neurological deficits by painless Nerve Growth Factor in a mouse model of Rett Syndrome
Neural precursor/stem cell-based therapy for Rett syndrome
Pharmacological modulation of neuronal activity for the treatment of Rett syndrome
Mirtazapine rescues neuronal atrophy in Rett syndrome through TrkB transactivation via LPA-receptor
Treatment with the CB1R antagonist rimonabant rescues brain mitochondrial dysfunction via inhibition of intra-mitochondrial protein kinase A signalling in a mouse model of Rett syndrome
The intrinsic properties of somatostatin interneurons in a Mecp2-deficient mouse model of Rett syndrome
FENS Forum 2024
The modulation of p75 neurotrophin receptor reduces oxidative stress and inflammation in a cellular model of Rett syndrome
FENS Forum 2024
The use of a shortened MeCP2 protein construct in Rett syndrome protein replacement therapy
FENS Forum 2024
In vitro Rett syndrome model based on MeCP2 knockdown in iPSC-derived neurons
FENS Forum 2024
In vitro analysis of mitochondrial abnormalities and oxinflammatory mechanisms involved in Rett Syndrome
FENS Forum 2024
In-silico prediction of novel targets for mirtazapine in Rett syndrome
FENS Forum 2024
Investigation of protein replacement therapy for Rett Syndrome using directly reprogrammed neurons
FENS Forum 2024
Testing the therapeutic effects of autophagy enhancement in a Rett syndrome mouse model
FENS Forum 2024
rett syndrome coverage
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