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Dysregulation and restoration of translational homeostasis in fragile X syndrome

Nature Reviews Neuroscience volume 16, pages 595–605 (2015)Cite this article

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Key Points

  • Fragile X syndrome (FXS) is an X-linked heritable form of intellectual disability with a high incidence of autism spectrum disorder (ASD) characteristics. FXS is recognized as the most commonly inherited form of intellectual disability and ASD.

  • FXS is a CGG-repeat disease that causes silencing of the fragile X mental retardation 1 (FMR1) gene and loss of its protein product, FMR protein (FMRP).

  • FMRP is an mRNA-binding protein that mainly acts as a translational repressor. Excessive basal protein synthesis has been reported in FXS model mice that lack Fmr1 as well as in cells from individuals with FXS.

  • Ten studies have reported genetic rescue of FXS pathophysiologies in Fmr1-knockout mice. Eight of these genetic rescues normalize excessive protein synthesis in the FXS model mice, consistent with the hypothesis that resetting translational homeostasis is central to the rescue mechanisms.

  • If resetting translational homeostasis is central to the rescue of FXS pathophysiologies, it suggests that there are specific mRNAs whose translation is elevated in FXS and normalized in the genetic rescues. These mRNAs are likely to have profound implications for the aetiology of FXS.

Abstract

Fragile X syndrome (FXS), the most-frequently inherited form of intellectual disability and the most-prevalent single-gene cause of autism, results from a lack of fragile X mental retardation protein (FMRP), an RNA-binding protein that acts, in most cases, to repress translation. Multiple pharmacological and genetic manipulations that target receptors, scaffolding proteins, kinases and translational control proteins can rescue neuronal morphology, synaptic function and behavioural phenotypes in FXS model mice, presumably by reducing excessive neuronal translation to normal levels. Such rescue strategies might also be explored in the future to identify the mRNAs that are critical for FXS pathophysiology.

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Figure 1: Translational control pathways that are dysregulated in FXS.
Figure 2: FMRP may stall polyribosomes to reduce the rate of translation elongation.
Figure 3: Involvement of CPEB in mediating FMRP activity.
Figure 4: Identification of dysregulated mRNAs that are rescued by pharmacological or genetic manipulations in FXS model mice.

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Acknowledgements

This work was supported by Fragile X Syndrome Research Center grant HD082013 from the US National Institutes of Health.

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Authors and Affiliations

  1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01545, Massachusetts, USA

    Joel D. Richter

  2. Department of Cell Biology, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Gary J. Bassell

  3. Center for Neural Science, New York University, New York City, 10003, New York, USA

    Eric Klann

Authors
  1. Joel D. Richter
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  2. Gary J. Bassell
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  3. Eric Klann
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Correspondence to Eric Klann.

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PowerPoint slides

Glossary

Alternative splicing

A form of nuclear pre-mRNA splicing in which different exons can be included into the mature mRNA.

RNA editing

A post-transcriptional event in which ribonucleotides are modified; for example, from adenosine to inosine or from cytosine to uridine.

RNA-induced silencing complex

(RISC). A complex of a microRNA and Argonaute (plus associated factors, such as GW182) that silences mRNA expression by inhibiting translation and/or causing mRNA instability.

G-quartet

A guanosine-containing quadruplex structure in RNA that is thought to be a binding site for fragile X mental retardation protein.

Induced pluripotent stem cell

(iPSC). A type of stem cell that is produced by transducing a differentiated cell with certain transcription factors. iPSCs have the potential to be converted into any terminally differentiated cell type.

Polyribosomes

Functional units of protein synthesis made of several ribosomes attached along the length of an mRNA molecule.

Cis

A chemical term denoting a structure in which, for example, two atoms reside on the same side of a particular structure (in contrast to trans, which refers to atoms on different sides of a structure). In molecular biology, cis refers to a sequence of DNA or RNA that often serves as a binding site for a trans-acting factor, such as a protein.

Long-term depression

(LTD). A form of synaptic plasticity that results in a long-lasting decrease in the strength of synaptic transmission. LTD is exaggerated in fragile X mental retardation 1-knockout mice.

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Richter, J., Bassell, G. & Klann, E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci 16, 595–605 (2015). https://doi.org/10.1038/nrn4001

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