A5063825725- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Neuroscience and Neuropharmacology Research
- Congenital heart defects research
- Genomics and Chromatin Dynamics
- Genetic Neurodegenerative Diseases
- Autism Spectrum Disorder Research
- Cellular transport and secretion
- Peptidase Inhibition and Analysis
- Mitochondrial Function and Pathology
- Neuroinflammation and Neurodegeneration Mechanisms
- Hearing, Cochlea, Tinnitus, Genetics
- Bipolar Disorder and Treatment
- Neural dynamics and brain function
- Ion channel regulation and function
- Retinal Development and Disorders
- RNA regulation and disease
- Neurological disorders and treatments
- RNA and protein synthesis mechanisms
- Diet and metabolism studies
- Receptor Mechanisms and Signaling
- Alzheimer's disease research and treatments
- Chromosomal and Genetic Variations
- Protein Degradation and Inhibitors
University of Edinburgh
2016-2024
Simons Initiative for the Developing Brain
2024
University of Coimbra
2011-2022
Discovery Centre
2018
Boston Children's Hospital
2014
Harvard University
2014
Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used ribosome affinity purification (TRAP) and RNA-seq identify mistranslating in CA1 pyramidal neurons FX mouse model (Fmr1-/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find...
Brief, early treatments with lovastatin provide long-lasting rescue of associative memory deficits in a rat model Fragile X.
Abstract Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation mRNAs downstream mGlu 1/5 activation. Here, we use combination CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify overtranslating supporting exaggerated -induced long-term depression (mGluR-LTD) mouse model ( Fmr1 −/y ). Our results significant increase ribosomal proteins (RPs)...
Abstract Background Mutations in the X-linked gene cyclin-dependent kinase-like 5 ( CDKL5 ) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated other models of monogenic forms spectrum disorders ID is often linked to epilepsy behavioural abnormalities. Many individuals with deficiency (CDD) have null mutations complete loss protein, therefore current study we used...
Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and risk factor for autism. encodes synaptic GTPase-activating protein (GAP) that has both signaling scaffolding roles. Most pathogenic variants predicted to result haploinsufficiency. However, some affected individuals carry missense mutations its calcium/lipid binding (C2) GAP domains, suggesting many clinical features from loss functions carried out by these domains. To test this hypothesis, we targeted the...
During development, neurons are constantly refining their connections in response to changes activity. Experience-dependent plasticity is a key form of synaptic plasticity, involving α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) accumulation at synapses. Here, we report critical role for the AMPAR auxiliary subunit stargazin this plasticity. We show that functional retinogeniculate synapse and absence stargazin, refinement specifically disrupted during...
Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved ubiquitously distributed tissues, toxicity targets only defined neuronal populations. Changes an expanded polyglutamine protein possibly influenced endogenous cellular mechanisms, which may be harnessed to produce neuroprotection. Here, we show that ataxin-3, spinocerebellar ataxia type 3, also known as...
In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in expression not observed. Here, we tested whether drives compensatory rise degradation that protective for FX mouse model (Fmr1-/y) neurons. Surprisingly, although find significant through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing activity with bortezomib corrects hippocampal and...
The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause autism and intellectual disability (ID). therapeutic efficacy is being tested clinical trials for FX; however, the structurally similar simvastatin has been proposed as an alternative due to increased potency brain penetrance. Here, we perform side-by-side comparison effects treatment on two core Fmr1 -/y mice versus WT littermates:...
Abstract Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory (TARPs) auxiliary regulate crucial aspects function. Here, we investigate a mutant form TARP family member stargazin, described an ID patient. Molecular dynamics analyses predicted ID-associated stargazin variant, V143L, weakens overall interface AMPAR:stargazin complex and...
Synaptic scaling is a form of homeostatic plasticity that critical for maintaining neuronal activity within dynamic range, and which alters synaptic strength through changes in postsynaptic AMPA-type glutamate receptors. Homeostatic down excitatory synapses has been shown to occur during sleep, contribute synapse remodeling memory consolidation, but the underlying mechanisms are only partially known. Here, we report downscaling cortical neurons accompanied by dephosphorylation transmembrane...
Significance statement The statin drug lovastatin normalizes excessive protein synthesis and thereby ameliorates pathological changes in animal models of Fragile X Syndrome (FX), the most commonly identified genetic cause autism. Recently, we compared efficacy to more potent brain-penetrant simvastatin for correcting phenotypes Fmr1-/y mouse (Muscas et al., 2019). Surprisingly, find worsens has no impact on audiogenic seizures (AGS) mice, suggesting it does not work a similar fashion...
Identifying causative variants in cis -regulatory elements (CRE) neurodevelopmental disorders has proven challenging. We have used vivo functional analyses to categorize rigorously filtered CRE a clinical cohort that is plausibly enriched for mutations: 48 unrelated males with family history consistent X-linked intellectual disability (XLID) whom no detectable cause could be identified the coding regions of X chromosome (chrX). Targeted sequencing all chrX six rare five affected individuals...
cfos is an immediate early gene commonly used to identify neuronal activation. After loud sound stimulation, neurons in the inferior colliculus are activated and cFos expressed nucleus. Here, we present a protocol for quantifying activity response auditory stimulation using immunostaining mouse colliculus. We then detail procedures image acquisition analysis. For complete details on use execution of this protocol, please refer Louros et al.
Abstract The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause autism and intellectual disability. therapeutic efficacy is being tested clinical trials for FX, however the structurally similar simvastatin has been proposed as an alternative due to increased potency brain penetrance. Here, we perform side-by-side comparison effects treatment on two core Fmr1 -/y mouse model. We find that while...
Abstract Undiagnosed neurodevelopmental disease is significantly associated with rare variants in cis -regulatory elements (CRE) but demonstrating causality challenging as target gene consequences may differ from a causative variant affecting the coding region. Here, we address this challenge by applying procedure to discriminate likely diagnostic regulatory those of neutral/low-penetrant effect. We identified six CRE using targeted and whole genome sequencing 48 unrelated males apparent...
Abstract Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation mRNAs downstream mGlu 1/5 activation. Here, we use combination CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify overtranslating supporting exaggerated -induced long-term depression (mGluR-LTD) mouse model ( Fmr1 -/y ). Surprisingly, our results robust ribosomal proteins (RPs)...