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"Fragile"
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FMRP regulates postnatal neuronal migration via MAP1B
The fragile X syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of autism spectrum disorder. FXS results from the absence of the RNA-binding protein FMRP (fragile X messenger ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal rostral migratory stream (RMS) neurons in Fmr1 -null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary Fmrp mRNA target implicated in these migratory defects is microtubule-associated protein 1B (MAP1B). Knocking down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.
Journal Article
The carriers : what the fragile X gene reveals about family, heredity, and scientific discovery
\"Fragile X syndrome is a genetic condition that causes a range of neurodevelopmental problems including learning disabilities and cognitive impairment. Boys with the condition are more likely to be born fully affected by it, while women who are seemingly unaffected carriers have an increased risk of giving birth to an affected child. Recent research indicates that Fragile X syndrome is highly unusual in the world of genetic disorders, in that carriers, who were previously thought to show no symptoms at all, are in fact affected in their own ways: into adulthood, they can develop personality and emotional changes, tremors, and difficulty walking. The title characters in The Carriers, then, are the previous generations--mothers and grandparents--of fully affected Fragile X patients. This book aims to tell the stories of how families are affected by this genetic disorder over generations, as well as the initial science that discovered it and the current science that's teaching us how Fragile X is affecting silent carriers in ways that weren't previously recognized. Understanding psychiatric symptoms in premutation carriers is complicated by the fact that many are caring for children with Fragile X syndrome and fathers with the tremor/ataxia symptom (difficulty walking). This story particularly highlights women, who are often the carriers in question and also the genetic researchers achieving scientific breakthroughs\"-- Provided by publisher.
Book
The translation of translational control by FMRP: therapeutic targets for FXS
In this review, the authors discuss the function of fragile X mental retardation protein (FMRP) in regulating the synthesis of plasticity-related target proteins. The authors review the known mRNA targets of FMRP and discuss the potential therapeutic implications of this research.
De novo
protein synthesis is necessary for long-lasting modifications in synaptic strength and dendritic spine dynamics that underlie cognition. Fragile X syndrome (FXS), characterized by intellectual disability and autistic behaviors, holds promise for revealing the molecular basis for these long-term changes in neuronal function. Loss of function of the fragile X mental retardation protein (FMRP) results in defects in synaptic plasticity and cognition in many models of the disease. FMRP is a polyribosome-associated RNA-binding protein that regulates the synthesis of a set of plasticity-reated proteins by stalling ribosomal translocation on target mRNAs. The recent identification of mRNA targets of FMRP and its upstream regulators, and the use of small molecules to stall ribosomes in the absence of FMRP, have the potential to be translated into new therapeutic avenues for the treatment of FXS.
Journal Article
Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible
To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1–/–) mouse model of Fragile X syndrome. Using a go/no-go task and in vivo two-photon calcium imaging, we find that impaired visual discrimination in Fmr1–/– mice correlates with marked deficits in orientation tuning of principal neurons and with a decrease in the activity of parvalbumin interneurons in primary visual cortex. Restoring visually evoked activity in parvalbumin cells in Fmr1–/– mice with a chemogenetic strategy using designer receptors exclusively activated by designer drugs was sufficient to rescue their behavioral performance. Strikingly, human subjects with Fragile X syndrome exhibit impairments in visual discrimination similar to those in Fmr1–/– mice. These results suggest that manipulating inhibition may help sensory processing in Fragile X syndrome.
Journal Article
Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.
Journal Article
The molecular biology of FMRP: new insights into fragile X syndrome
Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that — when epigenetically inactivated by a triplet nucleotide repeat expansion — causes the neurodevelopmental disorder fragile X syndrome (FXS). FMRP is a widely expressed RNA-binding protein with activity that is essential for proper synaptic plasticity and architecture, aspects of neural function that are known to go awry in FXS. Although the neurophysiology of FXS has been described in remarkable detail, research focusing on the molecular biology of FMRP has only scratched the surface. For more than two decades, FMRP has been well established as a translational repressor; however, recent whole transcriptome and translatome analyses in mouse and human models of FXS have shown that FMRP is involved in the regulation of nearly all aspects of gene expression. The emerging mechanistic details of the mechanisms by which FMRP regulates gene expression may offer ways to design new therapies for FXS.Inactivation of the gene encoding fragile X mental retardation protein (FMRP) drives the impairments in brain development and function that underlie fragile X syndrome. Richter and Zhao illustrate how innovative genetic and molecular biology tools have enhanced our understanding of both FMRP’s function and the causes of fragile X syndrome pathophysiology.
Journal Article
Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results
Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications.
Journal Article
A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)
Background
Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy.
Design
CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS.
Methods
Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-C
FXS
) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the
FMR1
methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the
FMR1
gene, in whom
FMR1
gene silencing is most likely.
Results
A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the
FMR1
promoter and full mutation of
FMR1
. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of
FMR1
(nominal
P
= 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression‐Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal
P
-values:
P
= 0.038,
P
= 0.028, and
P
= 0.002). Similar results were seen in patients with 100% methylation of
FMR1
. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%).
Conclusions
In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the
FMR1
gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe.
Trial registration
The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).
Journal Article