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Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment / Kagistia Hana UTAMI in Molecular Autism, 11 (2020)
[article]
Titre : Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment Type de document : Texte imprimé et/ou numérique Auteurs : Kagistia Hana UTAMI, Auteur ; Nur Amirah Binte Mohammad YUSOF, Auteur ; Jing Eugene KWA, Auteur ; Ulla-Kaisa PETERI, Auteur ; Maija L. CASTRÉN, Auteur ; Mahmoud A. POULADI, Auteur Article en page(s) : 41 p. Langues : Anglais (eng) Mots-clés : Fragile X syndrome Human stem cells Protein synthesis Therapy interest. Index. décimale : PER Périodiques Résumé : FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. En ligne : http://dx.doi.org/10.1186/s13229-020-00350-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 41 p.[article] Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment [Texte imprimé et/ou numérique] / Kagistia Hana UTAMI, Auteur ; Nur Amirah Binte Mohammad YUSOF, Auteur ; Jing Eugene KWA, Auteur ; Ulla-Kaisa PETERI, Auteur ; Maija L. CASTRÉN, Auteur ; Mahmoud A. POULADI, Auteur . - 41 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 41 p.
Mots-clés : Fragile X syndrome Human stem cells Protein synthesis Therapy interest. Index. décimale : PER Périodiques Résumé : FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. En ligne : http://dx.doi.org/10.1186/s13229-020-00350-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome / Magdalena KALINOWSKA in Molecular Autism, 13 (2022)
[article]
Titre : Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Magdalena KALINOWSKA, Auteur ; Mathijs B. VAN DER LEI, Auteur ; Michael KITIASHVILI, Auteur ; Maggie MAMCARZ, Auteur ; Mauricio M. OLIVEIRA, Auteur ; Francesco LONGO, Auteur ; Eric KLANN, Auteur Article en page(s) : 29 p. Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder/metabolism Disease Models, Animal Fragile X Mental Retardation Protein/genetics/metabolism Fragile X Syndrome/genetics/metabolism/pathology Mice Mice, Knockout Neurons/metabolism/pathology Parvalbumins/metabolism RNA, Messenger/metabolism Somatostatin/metabolism Autism Behavior Fmrp Fragile X syndrome Inhibitory neurons Protein synthesis Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. METHODS: We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. RESULTS: De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. LIMITATIONS: The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. CONCLUSIONS: Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00509-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491
in Molecular Autism > 13 (2022) . - 29 p.[article] Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome [Texte imprimé et/ou numérique] / Magdalena KALINOWSKA, Auteur ; Mathijs B. VAN DER LEI, Auteur ; Michael KITIASHVILI, Auteur ; Maggie MAMCARZ, Auteur ; Mauricio M. OLIVEIRA, Auteur ; Francesco LONGO, Auteur ; Eric KLANN, Auteur . - 29 p.
Langues : Anglais (eng)
in Molecular Autism > 13 (2022) . - 29 p.
Mots-clés : Animals Autism Spectrum Disorder/metabolism Disease Models, Animal Fragile X Mental Retardation Protein/genetics/metabolism Fragile X Syndrome/genetics/metabolism/pathology Mice Mice, Knockout Neurons/metabolism/pathology Parvalbumins/metabolism RNA, Messenger/metabolism Somatostatin/metabolism Autism Behavior Fmrp Fragile X syndrome Inhibitory neurons Protein synthesis Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. METHODS: We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. RESULTS: De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. LIMITATIONS: The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. CONCLUSIONS: Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00509-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Titre : FMRP and the Pathophysiology of Fragile X Syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Stephanie A. BARNES, Auteur ; Sophie R. THOMSON, Auteur ; Peter C. KIND, Auteur ; Emily K. OSTERWEIL, Auteur Année de publication : 2016 Importance : p.113-128 Langues : Anglais (eng) Mots-clés : ERK FMR1 FMRP Fragile X mGluR1/5 Protein synthesis Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Fragile X syndrome (FXS) is a single-gene disorder that is the most prevalent heritable cause of intellectual disability and one of the most common single-gene causes of autism spectrum disorder (ASD). Although there is a clear genetic origin of FXS, there is still much to learn about the cellular and physiological consequences of FMR1 mutation. This knowledge is critical to the development of treatments to target the core pathophysiology of FXS. In this chapter, we summarize what is known about the function of the FMR1 gene and the encoded Fragile X mental retardation protein and describe the major cellular and neurophysiological phenotypes observed in the FXS mouse model. We then discuss evidence supporting the metabotropic glutamate receptor (mGluR) theory of Fragile X, which states that dysregulated protein synthesis downstream of mGluR1/5 is a core contributor to the pathogenesis of FXS. The remainder of the chapter will be devoted to discussing the clinical implications of this research and its relevance to the wider ASD population. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00008-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 FMRP and the Pathophysiology of Fragile X Syndrome [Texte imprimé et/ou numérique] / Stephanie A. BARNES, Auteur ; Sophie R. THOMSON, Auteur ; Peter C. KIND, Auteur ; Emily K. OSTERWEIL, Auteur . - 2016 . - p.113-128.
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Langues : Anglais (eng)
Mots-clés : ERK FMR1 FMRP Fragile X mGluR1/5 Protein synthesis Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Fragile X syndrome (FXS) is a single-gene disorder that is the most prevalent heritable cause of intellectual disability and one of the most common single-gene causes of autism spectrum disorder (ASD). Although there is a clear genetic origin of FXS, there is still much to learn about the cellular and physiological consequences of FMR1 mutation. This knowledge is critical to the development of treatments to target the core pathophysiology of FXS. In this chapter, we summarize what is known about the function of the FMR1 gene and the encoded Fragile X mental retardation protein and describe the major cellular and neurophysiological phenotypes observed in the FXS mouse model. We then discuss evidence supporting the metabotropic glutamate receptor (mGluR) theory of Fragile X, which states that dysregulated protein synthesis downstream of mGluR1/5 is a core contributor to the pathogenesis of FXS. The remainder of the chapter will be devoted to discussing the clinical implications of this research and its relevance to the wider ASD population. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00008-X Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Exemplaires
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