Signals, Synapses, and Synthesis: How New Proteins Control Plasticity

Localization of mRNAs to dendrites and local protein synthesis afford spatial and temporal regulation of gene expression and endow synapses with the capacity to autonomously alter their structure and function. Emerging evidence indicates that RNA binding proteins, ribosomes, translation factors and mRNAs encoding proteins critical to synaptic structure and function localize to neuronal processes. RNAs are transported into dendrites in a translationally quiescent state where they are activated by synaptic stimuli. Two RNA binding proteins that regulate dendritic RNA delivery and translational repression are cytoplasmic polyadenylation element binding protein and fragile X mental retardation protein (FMRP). The fragile X syndrome (FXS) is the most common known genetic cause of autism and is characterized by the loss of FMRP. Hallmark features of the FXS include dysregulation of spine morphogenesis and exaggerated metabotropic glutamate receptor-dependent long term depression, a cellular substrate of learning and memory. Current research focuses on mechanisms whereby mRNAs are transported in a translationally repressed state from soma to distal process and are activated at synaptic sites in response to synaptic signals

Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders

The Fragile X syndrome (FXS) is a leading cause of intellectual disability (ID) and autism. The disease is caused by mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein playing multiple functions in RNA metabolism. The expression of a large set of neuronal mRNAs is altered when FMRP is lost, thus causing defects in neuronal morphology and physiology. FMRP regulates mRNA stability, dendritic targeting, and protein synthesis. At synapses, FMRP represses protein synthesis by forming a complex with the Cytoplasmic FMRP Interacting Protein 1 (CYFIP1) and the cap-binding protein eIF4E. Here, we review the clinical, genetic, and molecular aspects of FXS with a special focus on the receptor signaling that regulates FMRP-dependent protein synthesis. We further discuss the FMRP–CYFIP1 complex and its potential relevance for ID and autism

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

© 2015 Elsevier Inc. The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes. Pasciuto etal. show that dual dysregulation of APP and ADAM10, during a critical period of postnatal development, leads to overproduction of sAPPα. Modulation of ADAM10 activity re-establishes physiological sAPPα levels and ultimately ameliorates FXS molecular, synaptic, and behavioral deficits.Stichting Alzheimer Onderzoek -Fondation Recherche Maladie Alzheimer (SAO-FMA), Vlaams Instituut voor Biotechnologie (VIB), KU Leuven (Opening the Future), European Research Projects on Neurodevelopmental Disorders NEURON ERA-NET, Associazione Italiana Sindrome X Fragile, Compagnia San Paolo, and Fondation Jerome Lejeune to C.B., a European Research Council Grant ERC-2010-AG_268675 to B.D.S.; a Methusalem grant of the KU Leuven/Flemish Government to B.D.S. and C.D. B.D.S. is supported by the Bax-Vanluffelen Chair for Alzheimer’s Disease. C.B. and B.D.S. are supported by ‘‘Opening the Future’’ of the Leuven Universiteit Fonds (LUF). Deutsche Forschungsgemeinschaft (DFG) (MU 1457/8-1; 1457/9-1)Peer Reviewe

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the FMR1 Gene

Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the FMR1 gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5′UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes

Palafitum

[Resumen] Palafitum es un videojuego de plataformas en 2D. A diferencia de otros videojuegos del mismo género, Palafitum aporta nuevas mecánicas que enriquecen tanto la narrativa como la jugabilidad. El propósito del videojuego no es meramente entretener al espectador, sino abordar temas esenciales como el respeto por la naturaleza. Además, también pretende acercar valores éticos que salen a relucir cuando se habla de las guerras causadas por la obtención de recursos naturales. Todo esto, acompañado de una estética propia y cuidada que refuerza visualmente lo que la historia pretende contar.[Resumo] Palafitum é un videoxogo de plataformas en 2D. A diferenza doutros videoxogos do mesmo xénero, Palafitum achega novas mecánicas que enriquecen tanto a narrativa como a xogabilidade. O propósito do videoxogo non é meramente entreter ao espectador, senón abordar temas esenciais como o respecto pola natureza. Ademais, tamén pretende achegar valores éticos que saen a relucir cando se fala das guerras causadas pola obtención de recursos naturais. Todo isto, acompañado dunha estética propia e coidada que reforza visualmente o que a historia pretende contar.[Abstract] Palafitum is a 2D platform video game. Unlike other games of the same genre, Palafitum brings new mechanics that enrich both narrative and gameplay. The purpose of this game is not merely to entertain the viewer, however to address fundamental issues such as respect for nature. In addition, it also aims to bring ethical values to light, for instance wars which are unleashed to obtain natural resources. All the before mentioned, accompanied by a personalized and meticulous aesthetics visually reinforce what the story tries to convey.Traballo fin de grao (UDC.COM). Comunicación audiovisual. Curso 2018/201

The Fragile X Mental Retardation Protein Regulates RIPK1 and Colorectal Cancer Resistance to Necroptosis

Background & aims: The fragile X mental retardation protein (FMRP) affects multiple steps of the mRNA metabolism during brain development and in different neoplastic processes. However, the contribution of FMRP in colon carcinogenesis has not been investigated. Methods: FMR1 mRNA transcript and FMRP protein expression were analyzed in human colon samples derived from patients with sporadic colorectal cancer (CRC) and healthy subjects. We used a well-established mouse model of sporadic CRC induced by azoxymethane to determine the possible role of FMRP in CRC. To address whether FMRP controls cancer cell survival, we analyzed cell death pathway in CRC human epithelial cell lines and in patient-derived colon cancer organoids in presence or absence of a specific FMR1 antisense oligonucleotide or siRNA. Results: We document a significant increase of FMRP in human CRC relative to non-tumor tissues. Next, using an inducible mouse model of CRC, we observed a reduction of colonic tumor incidence and size in the Fmr1 knockout mice. The abrogation of FMRP induced spontaneous cell death in human CRC cell lines activating the necroptotic pathway. Indeed, specific immunoprecipitation experiments on human cell lines and CRC samples indicated that FMRP binds receptor-interacting protein kinase 1 (RIPK1) mRNA, suggesting that FMRP acts as a regulator of necroptosis pathway through the surveillance of RIPK1 mRNA metabolism. Treatment of human CRC cell lines and patient-derived colon cancer organoids with the FMR1 antisense resulted in up-regulation of RIPK1. Conclusions: Altogether, these data support a role for FMRP in controlling RIPK1 expression and necroptotic activation in CRC

Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic Inputs

Glycine receptors (GlyRs) containing the α2 subunit are highly expressed in the developing brain, where they regulate neuronal migration and maturation, promote spontaneous network activity and subsequent development of synaptic connections. Mutations in GLRA2 are associated with autism spectrum disorder, but the underlying pathophysiology is not described yet. Here, using Glra2-knockout mice, we found a GlyR-dependent effect on neonatal spontaneous activity of dorsal striatum medium spiny neurons (MSNs) and maturation of the incoming glutamatergic innervation. Our data demonstrate that functional GlyRs are highly expressed in MSNs of one-week-old mice, but they do not generate endogenous chloride-mediated tonic or phasic current. Despite of that, knocking out the Glra2 severely affects the shape of action potentials and impairs spontaneous activity and the frequency of miniature AMPA receptor-mediated currents in MSNs. This reduction in spontaneous activity and glutamatergic signaling can attribute to the observed changes in neonatal behavioral phenotypes as seen in ultrasonic vocalizations and righting reflex. In adult Glra2-knockout animals, the glutamatergic synapses in MSNs remain functionally underdeveloped. The number of glutamatergic synapses and release probability at presynaptic site remain unaffected, but the amount of postsynaptic AMPA receptors is decreased. This deficit is a consequence of impaired development of the neuronal circuitry since acute inhibition of GlyRs by strychnine in adult MSNs does not affect the properties of glutamatergic synapses. Altogether, these results demonstrate that GlyR-mediated signaling supports neonatal spontaneous MSN activity and, in consequence, promotes the functional maturation of glutamatergic synapses on MSNs. The described mechanism might shed light on the pathophysiological mechanisms in GLRA2-linked autism spectrum disorder cases

Spatial control of nucleoporin condensation by fragile X-related proteins

Nucleoporins (Nups) build highly organized nuclear pore complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs. In the cytoplasm, the soluble Nups exist, but how their assembly is restricted to the NE is currently unknown. Here, we show that fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup condensates. Likewise, models of fragile X syndrome (FXS), characterized by a loss of FMRP, accumulate Nup granules. The Nup granule-containing cells show defects in protein export, nuclear morphology and cell cycle progression. Our results reveal an unexpected role for the FXR protein family in the spatial regulation of nucleoporin condensation