Fragile X Syndrome: from molecular pathology to therapy
Abstract
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability due to the silencing of the FMR1 gene encoding FMRP (Fragile X Mental Retardation Protein), an RNA-binding protein involved in different steps of RNA metabolism. Of particular interest is the key role of FMRP in translational regulation. Since the first functional characterizations of FMRP, its role has been underlined by its association with actively translating polyribosomes. Furthermore, a plethora of mRNA targets of FMRP have been identified. In the absence of FMRP the deregulation of translation/transport/stability of these mRNAs has a cascade effect on many pathways, resulting into the final phenotype. We review here a set of targets of FMRP (mRNAs and proteins) that may have an impact on the FXS phenotype by deregulating some key cellular processes, such as translation, cytoskeleton remodeling and oxidative stress. The manipulation of these abnormal pathways by specific drugs may represent new therapeutic opportunities for FXS patients.
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CYFIP1 has a positive role in pS6-mediated translational regulation, opposite to FMRP.
“This finding shows a positive role for CYFIP1 in pS6-mediated translational regulation, which is an opposite function with respect to FMRP (Sharma et al., 2010; Maurin et al., 2014).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Maurin et al., 2014
The co-repressor activity of CYFIP1-FMRP does not affect G-quadruplex-containing mRNAs, which represent a subset of FMRP targets.
“We can thus conclude that the co-repressor activity of CYFIP1-FMRP does not affect G-quadruplex-containing mRNAs, which represent a subset of FMRP targets (Brown et al., 2001; Maurin et al., 2014; Suhl et al., 2015).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Maurin et al., 2014
FMRP is not only involved in translation regulation and CYFIP1 is a component of complexes that do not contain FMRP.
“These conclusions are consistent with the fact that FMRP is, indeed, not only involved in translation regulation (Maurin et al., 2014) and CYFIP1 is a component of complexes that do not contain FMRP (Abekhoukh and Bardoni, 2014; Chen et al., 2014).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Maurin et al., 2014
FMRP is involved in RNA transport along neurites and between nucleus and cytoplasm.
“In addition, this protein is involved in RNA transport along neurites and between nucleus and cytoplasm (Maurin et al., 2014).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Maurin et al., 2014
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CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome
Abekhoukh, S., & Bardoni, B. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00081 · Cited by 110 · see citing works
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“…effect, F 1,37 =1.52 P =0.225; genotype-Sh interaction, F 1,37 =7.92, * P =0.008, followed by LSD post hoc test, n =11,10,11,9). shows a positive role for CYFIP1 in pS6-mediated translational regulation, which is an opposite function with respect to FMRP (Sharma et al., 2010; Maurin et al., 2014).”
InfluentialSelf-citationBrain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome
Parente, M., Tonini, C., Buzzelli, V., Carbone, E., Trezza, V., & Pallottini, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063408 · Cited by 11 · see citing works
“Additionally, it was found that FMRP targets a subset of mRNA encoding proteins critically involved in lipid synthesis and transport [6].”
BackgroundInfluential
- Authors
- Maurin, T., Zongaro, S., & Bardoni, B.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Bardoni, Barbara
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 46
- Pages
- 242-255
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W1991476271
- Cited by
- 113
- References
- 17
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 8 · 2023: 11 · 2022: 12 · 2021: 11 · 2020: 10 · 2019: 7 · 2018: 17 · 2017: 11 · 2016: 3 · 2015: 8 · 2014: 10
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- INSERM
- CNRS LIA NEOGENEX
- Agence Nationale de la Recherche (ANR-11-LABX-0028-01, Blanc SVSE4-2012, Blanc SVSE8-2012)
- Fondation Jérôme Lejeune
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- fragile X syndrome, FMRP, FMR1 gene, intellectual disability, translational regulation, RNA-binding proteins, mRNA targets, polysomes, cytoskeletal remodeling, oxidative stress
- MeSH terms
- Cytoskeleton, Fragile X Syndrome, Gene Expression Regulation, Humans, Models, Genetic, Oxidative Stress, MicroRNAs, Fragile X Messenger Ribonucleoprotein 1, Molecular Targeted Therapy
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