Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome

Seo, Sang Soo; Louros, Susana R.; Anstey, Natasha; Gonzalez‐Lozano, Miguel A.; Harper, Callista B.; Verity, Nicholas; Dando, Owen; Thomson, Sophie R.; Darnell, Jennifer C.; Kind, P.; Li, Ka Wan; Osterweil, Emily K.

doi:10.1038/s41467-022-30979-0

Cited by 20 publications

(9 citation statements)

References 88 publications

(116 reference statements)

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“…These data are corroborated by previous Ribo-tag studies of Fmr1 KO hippocampal cells, which similarly showed that 11/12 differentially expressed FMRP targets are reduced rather than increased in expression ( Ceolin et al 2017 ). Our findings here are similarly consistent with observations that FMRP CLIP targets have concordantly reduced ribosome footprints ( Das Sharma et al 2019 ), that FMRP preferentially binds to long transcripts ( Sawicka et al 2019 ; Li et al 2020 ), and that the protein levels of large proteins are reduced rather than increased in the Fmr1 KO hippocampal proteome ( Seo et al 2022 ). Our data are also consistent with other prior reports that FMRP activates the translation of its targets ( Bechara et al 2009 ; Tabet et al 2016 ).…”

Section: Discussionsupporting

confidence: 90%

FMRP-dependent production of large dosage-sensitive proteins is highly conserved

et al. 2022

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Mutations in FMR1 are the most common heritable cause of autism spectrum disorder. FMR1 encodes an RNA-binding protein, FMRP, which binds to long, autism-relevant transcripts and is essential for normal neuronal and ovarian development. In contrast to the prevailing model that FMRP acts to block translation elongation, we previously found that FMRP activates the translation initiation of large proteins in Drosophila oocytes. We now provide evidence that FMRP-dependent translation is conserved and occurs in the mammalian brain. Our comparisons of the mammalian cortex and Drosophila oocyte ribosome profiling data show that translation of FMRP-bound mRNAs decreases to a similar magnitude in FMRP-deficient tissues from both species. The steady-state levels of several FMRP targets were reduced in the Fmr1 KO mouse cortex, including a ∼50% reduction of Auts2, a gene implicated in an autosomal dominant autism spectrum disorder. To distinguish between effects on elongation and initiation, we used a novel metric to detect the rate-limiting ribosome stalling. We found no evidence that FMRP target protein production is governed by translation elongation rates. FMRP translational activation of large proteins may be critical for normal human development, as more than 20 FMRP targets including Auts2 are dosage sensitive and are associated with neurodevelopmental disorders caused by haploinsufficiency.

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Section: Discussionsupporting

confidence: 90%

FMRP-dependent production of large dosage-sensitive proteins is highly conserved

et al. 2022

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“…We examined the protein expression profiles of mature hiPSC‐ and hESC‐astrocytes using LC–MS and identified several dysregulated pathways using IPA. Some of our findings, such as dysregulated ribosomes and altered translation while expected based on the literature (Li et al, 2020; Seo et al, 2022), are still novel as shown here for astrocytes specifically. However, the proteomic analysis also pointed towards novel, previously unappreciated changes in FXS astrocytes which we have validated.…”

Section: Discussionsupporting

confidence: 76%

Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome

Ren

Burkovetskaya

Jung

et al. 2023

Glia

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Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human‐based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human‐based FXS model via differentiation of astrocytes from human‐induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles. We identified shortened cell cycle, enhanced Ca2+ signaling, impaired sterol biosynthesis, and pervasive alterations in the proteome of FXS astrocytes. Our work identified astrocytic impairments that could contribute to the pathogenesis of FXS and highlight astrocytes as a novel therapeutic target for FXS treatment.

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“…Therefore, we speculate that an increase in the expression of these transcripts translates into a higher ribosome loading, which is consistent with the observation of increased eIF4E-eIF4G interactions resulting from the loss of FMRP. Alternatively, it may reflect an imbalance in the translation of long versus short length mRNAs 81 .…”

Section: Discussionmentioning

confidence: 99%

Cell type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behaviour in fragile X syndrome model mice

Longo

Aryal

Anastasiades

et al. 2022

Preprint

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Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviours (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissected the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. We found that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum revealed differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings represent the first evidence of a cell-type specific impact of the loss of FMRP on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS.

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Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome

Cited by 20 publications

References 88 publications

FMRP-dependent production of large dosage-sensitive proteins is highly conserved

FMRP-dependent production of large dosage-sensitive proteins is highly conserved

Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome

Cell type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behaviour in fragile X syndrome model mice

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