Protein synthesis levels are increased in a subset of individuals with fragile X syndrome

Jacquemont, Sébastien; Pacini, Laura; Jønch, Aia Elise; Cencelli, Giulia; Rozenberg, Izabela; He, Yunsheng; D’Andrea, L.; Pedini, G; Eldeeb, Marwa; Willemsen, Rob; Gasparini, F.; Tassone, Flora; Hagerman, Randi J.; Gomez‐Mancilla, Baltazar; Bagni, Claudia

doi:10.1093/hmg/ddy099

Cited by 54 publications

(45 citation statements)

References 71 publications

(51 reference statements)

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“…4, Table 2 and additional le 4). Similar results were obtain with a larger cohort of broblasts derived from 21 FX males [37]. This lack of association in our study can easily be explained by the study design.…”

Section: Assessment Of Pbmcs Rate Of Protein Synthesis As a Biomarkersupporting

confidence: 91%

Rates of Protein Synthesis Are Reduced in Peripheral Blood Mononuclear Cells (PBMCs) from Fragile X Individuals

Dionne

Lortie

Gagnon

et al. 2020

Preprint

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BackgroundFragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). In animal model of FXS, the absence of FMRP leads to an aberrant rate of neuronal protein synthesis, which in turn is believed to be at the origin of defects regarding spine morphology and synaptic plasticity. Normalisation of protein synthesis in these models has been associated with a rescue of FXS behavioral and biochemicals phenotype, thus establishing the rate of protein synthesis as one of the most promising monitoring biomarker for FXS. However, rate of protein synthesis alteration in fragile X individuals is not well characterizedMethodWe applied a robust radiolabeled assay to measure rate of protein synthesis in freshly extracted peripheral blood mononuclear cells (PBMCs) and blood platelets. We ultimately settle on PBMCs to measure and compare rate of protein synthesis in 13 males with fragile X and 14 matched controls individuals. ResultsUsing this method, we measured a 26.9% decrease (p = 0,0193) in the rate of protein synthesis in fragile X individuals PBMCs. Furthermore, the rate of protein synthesis measurements obtained were highly reproducible, highlighting the robustness of the method. ConclusionOur work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X. Our results also support the finding of previous studies using brain PET imaging in Fragile X individuals. Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability.

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Section: Assessment Of Pbmcs Rate Of Protein Synthesis As a Biomarkersupporting

confidence: 91%

Rates of Protein Synthesis Are Reduced in Peripheral Blood Mononuclear Cells (PBMCs) from Fragile X Individuals

Dionne

Lortie

Gagnon

et al. 2020

Preprint

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“…The heterogeneity of FXS and ASDs in humans that underlies the individual variability may explain, at least in part, the lack of success of clinical trials aiming solely at decreasing protein synthesis. A recent study highlighted a large variability in the levels of protein synthesis in fibroblasts among patients diagnosed with FXS (Jacquemont et al, 2018). These findings suggest that future clinical trials should aim at stratifying the FXS population, define reliable endophenotypes, and then target them in personalized treatment strategies.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

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233

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Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders. ASDs and FXS: Causes and Clinical Features Approximately 1%-3% of the general population is affected by intellectual disabilities (IDs). IDs are neurodevelopmental disorders defined by significant limitations in intellectual functioning and adaptive behaviors and often exhibit comorbidity with autism (Mefford et al., 2012). Autism spectrum disorders (ASDs) are characterized by high phenotypic heterogeneity, comprising deficits in social interaction and communication as well as repetitive and stereotyped behaviors (

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“…First, cells were treated with Taxol (paclitaxel) for 16 h at 1 lM and then subsequently released from the mitotic block by addition of Hesperadin at 100 lM for 2 h. The two primary fibroblast cell lines from healthy individuals (control cell lines) were kindly provided by Hélène Puccio. The two primary fibroblast cell lines derived from FXS individuals are described in Jacquemont et al (2018). Human primary fibroblasts were cultured in DMEM (4.5 g/l glucose) supplemented with 10% FCS and gentamicin 40 ll/ml.…”

Section: Cell Lines and Cell Cycle Synchronizationsmentioning

confidence: 99%

Spatial control of nucleoporin condensation by fragile X‐related proteins

et al. 2020

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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.

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Protein synthesis levels are increased in a subset of individuals with fragile X syndrome

Cited by 54 publications

References 71 publications

Rates of Protein Synthesis Are Reduced in Peripheral Blood Mononuclear Cells (PBMCs) from Fragile X Individuals

Rates of Protein Synthesis Are Reduced in Peripheral Blood Mononuclear Cells (PBMCs) from Fragile X Individuals

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Spatial control of nucleoporin condensation by fragile X‐related proteins

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