1,721,037 research outputs found
Cooperativity in RNA-protein interactions: The complex is more than the sum of its partners
No full textMutations in RNA-binding proteins (RBPs) are often linked to specific neurological disorders, suggesting that each of these RBPs regulates a particular neuronal function. Instead, they recognise many mRNAs and often participate in various post-transcriptional processes. To gain specificity, RBPs bind to RNA in collaboration with other RBPs. This model also explains how an RBP can play diverse roles: many RBPs do not contain an effector domain, which joins the RNA-protein complex as an additional unit. Different complexes, even if anchored on the same RBP, recruit diverse effectors. Therefore, the combination of RBPs determines the fate of an mRNA. We argue that new experimental and bioinformatic paradigms are needed to elucidate the combination of RBPs acting on a given mRNA
Mislocalised FUS mutants stall spliceosomal snRNPs in the cytoplasm.
No full textGenes encoding RNA-binding proteins have frequently been implicated in various motor neuron diseases, but the particular step in RNA metabolism that is vulnerable in motor neurons remains unknown. FUS, a nuclear protein, forms cytoplasmic aggregates in cells affected by amyotrophic lateral sclerosis (ALS), and mutations disturbing the nuclear import of FUS cause the disease. It is extremely likely that the cytoplasmic aggregates are cytotoxic because they trap important factors; the nature of these factors, however, remains to be elucidated. Here we show that FUS associates in a neuronal cell line with SMN, the causative factor in spinal muscular atrophy (SMA). The two genes work on the same pathway, as FUS binds to spliceosomal snRNPs downstream of the SMN function. Pathogenic FUS mutations do not disturb snRNP binding. Instead, cytoplasmic mislocalisation of FUS causes partial mis-localisation of snRNAs to the cytoplasm, which in turn causes a change in the behaviour of the alternative splicing machinery. FUS, and especially its mutations, thus have a similar effect as SMN1 deletion in SMA, suggesting that motor neurons could indeed be particularly sensitive to changes in alternative splicing
The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x.
No full textThe RNA-binding protein Sam68 is involved in apoptosis, but its cellular mRNA targets and its mechanism of action remain unknown. We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alternative splicing. Depletion of Sam68 by RNA interference caused accumulation of antiapoptotic Bcl-x(L), whereas its up-regulation increased the levels of proapoptotic Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection. A point mutation in the RNA-binding domain of Sam68 influenced its splicing activity and subnuclear localization. Moreover, coexpression of ASF/SF2 with Sam68, or fusion with an RS domain, counteracted Sam68 splicing activity toward Bcl-x. Finally, Sam68 interacted with heterogenous nuclear RNP (hnRNP) A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated Bcl-x(s) splicing. Our results indicate that Sam68 plays a role in the regulation of Bcl-x alternative splicing and that tyrosine phosphorylation of Sam68 by Src-like kinases can switch its role from proapoptotic to antiapoptotic in live cells
mRNPs, polysomes or granules: FMRP in neuronal protein synthesis
Full text linkmRNA localization and regulated translation play central roles in neurite outgrowth and synaptic plasticity. A key molecule in these processes is the Fragile X mental retardation protein, FMRP, which is involved in the metabolism of neuronal mRNAs. Absence or mutation of FMRP leads to spine dysmorphogenesis and impairs synaptic plasticity. Studies that have mainly been performed on the mouse and Drosophila models for Fragile X Syndrome showed that FMRP is involved in translational regulation at synapses, but even 15 years after discovery of the FMR1 gene, the precise working mechanisms remain elusive.status: Publishe
Neuronal RNA-binding proteins in health and disease
No full textIn mammalian cells in general and in neurons in particular, mRNA maturation, translation, and degradation are highly complex and dynamic processes. RNA-binding proteins (RBPs) play crucial roles in all these events. First, they participate in the choice of pre-mRNA splice sites and in the selection of the polyadenylation sites, determining which of the possible isoforms is produced from a given precursor mRNA. Then, once in the cytoplasm, the protein composition of the RNP particles determines whether the mature mRNA is transported along the dendrites or the axon of a neuron to the synapses, how efficiently it is translated, and how stable it is. In agreement with their importance for neuronal function, mutations in genes that code for RBPs are associated with various neurological diseases. In this review, we illustrate how individual RBPs determine the fate of an mRNA, and we discuss how mutations in RBPs or perturbations of the mRNA metabolism can cause neurodegenerative disorders. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article
The intriguing case of motor neuron disease: ALS and SMA come closer
Full text linkMNDs (motor neuron diseases) form a heterogeneous group of pathologies characterized by the progressive degeneration of motor neurons. More and more genetic factors associated with MND encode proteins that have a function in RNA metabolism, suggesting that disturbed RNA metabolism could be a common underlying problem in several, perhaps all, forms of MND. In the present paper we review recent developments showing a functional link between SMN (survival of motor neuron), the causative factor of SMA (spinal muscular atrophy), and FUS (fused in sarcoma), a genetic factor in ALS (amyotrophic lateral sclerosis). SMN is long known to have a crucial role in the biogenesis and localization of the spliceosomal snRNPs (small nuclear ribonucleoproteins), which are essential assembly modules of the splicing machinery. Now we know that FUS interacts with SMN and pathogenic FUS mutations have a significant effect on snRNP localization. Together with other recently published evidence, this finding potentially links ALS pathogenesis to disturbances in the splicing machinery, and implies that pre-mRNA splicing may be the common weak point in MND, although other steps in mRNA metabolism could also play a role. Certainly, further comparison of the RNA metabolism in different MND will greatly help our understanding of the molecular causes of these devastating diseases
Cancer drug repurposing in autism spectrum disorder
No full textautism spectrum disorder (ASD) is a complex neurodevelopmental condition with uncertain origins. Understanding of the mechanisms underlying ASD re-mains limited, and treatments are lacking. genetic diversity complicates drug development. given the complexity and severity of ASD symptoms and the rising number of diagnoses, exploring novel therapeutic strategies is essential. here, we focus on shared molecular pathways between ASD and cancer and highlight recent progress on the repurposing of cancer drugs for ASD treatment, such as mTOR inhibitors, histone deacetylase inhibitors, and anti-inflammatory agents. we discuss how to improve trial design considering drug dose and patient age. lastly, the discussion explores the critical aspects of side effects, commercial factors, and the efficiency of drug-screening pipelines; all of which are essential considerations in the pursuit of repurposing cancer drugs for addressing core features of ASD
Modelling Learning and Memory in <i>Drosophila</i> to Understand Intellectual Disabilities
No full textNeurodevelopmental disorders (NDDs) include a large number of conditions such as Fragile X syndrome, autism spectrum disorders and Down syndrome, among others. They are characterized by limitations in adaptive and social behaviors, as well as intellectual disability (ID). Whole-exome and whole-genome sequencing studies have highlighted a large number of NDD/ID risk genes. To dissect the genetic causes and underlying biological pathways, in vivo experimental validation of the effects of these mutations is needed. The fruit fly, Drosophila melanogaster, is an ideal model to study NDDs, with highly tractable genetics, combined with simple behavioral and circuit assays, permitting rapid medium-throughput screening of NDD/ID risk genes. Here, we review studies where the use of well-established assays to study mechanisms of learning and memory in Drosophila has permitted insights into molecular mechanisms underlying IDs. We discuss how technologies in the fly model, combined with a high degree of molecular and physiological conservation between flies and mammals, highlight the Drosophila system as an ideal model to study neurodevelopmental disorders, from genetics to behavior.sponsorship: We apologize to our colleagues whose work could not be included due to limited space. This work was supported by KU Leuven Funds Opening the Future (Belgium), SNSF NCCR Synapsy 51NF40-158776, SNSF 310030182651 (Switzerland), Novartis Foundation for Medical Biological Researchand Canton Etat de Vaud (Switzerland), Fondazione Roma Terzo Pilastro Internazionale and Associazione Italiana Sindrome X Fragile to CB. AKK was a recipient of the Autism Speaks Meixner Translational Postdoctoral Fellowship (USA) and supported by the Autism Research Institute (USA) and the Fondation Sophie Afenduli (Switzerland). We acknowledge the Flybase for essential information and constant support of the fly community. We are grateful to Annick Crevoisier for administrative support and to Kris Dickson for suggestions and manuscript proofreading. We thank Gaia Tavosanis, Eleonora Rosina, Nuria Dominguez-Iturza and Adrian Lo for critical reading of the manuscript. (KU Leuven Funds Opening the Future (Belgium), SNSF NCCR Synapsy|51NF40-158776, SNSF (Switzerland)|310030182651, Novartis Foundation for Medical Biological Researchand Canton Etat de Vaud (Switzerland), Fondazione Roma Terzo Pilastro Internazionale, Associazione Italiana Sindrome X Fragile, Autism Speaks Meixner Translational Postdoctoral Fellowship (USA), Autism Research Institute (USA), Fondation Sophie Afenduli (Switzerland))status: Publishe
Crystal structure of the human U4/U6 small nuclear ribonucleoprotein particle-specific SnuCyp-20, a nuclear cyclophilin.
Full text linkThe cyclophilin SnuCyp-20 is a specific component of the human U4/U6 small nuclear ribonucleoprotein particle involved in the nuclear splicing of pre-mRNA. It stably associates with the U4/U6-60kD and -90kD proteins, the human orthologues of the Saccharomyces cerevisiae Prp4 and Prp3 splicing factors. We have determined the crystal structure of SnuCyp-20 art 2.0-Angstrom resolution by molecular replacement. Tbe structure of SnuCyp-20 closely resembles that of human cyclophilin A (hCypA), In particular, the catalytic centers of SnuCyp-20 and hCypA superimpose perfectly, which is reflected by the observed peptidyl-prolyl-cis/trans-isomerase activity of SnuCyp-20. The surface properties of both proteins, however, differ significantly. Apart from seven additional amino-terminal residues, the insertion of five amino acids in the loop alpha 1-beta 3 and of one amino acid in the loop alpha 2-beta 8 changes the conformations of both loops. The enlarged loop alpha 1-beta 3 is involved in the formation of a wide cleft with predominantly hydrophobic character, We propose that this enlarged loop is required for the interaction with the U4/U6-60kD protein
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