From FMRP Function to Potential Therapies for Fragile X Syndrome

Overview

Journal Neurochem Res

Specialties Chemistry
Neurology

Date 2013 Dec 19

PMID 24346713

Citations 29

Authors

Ferzin Sethna

Changjong Moon

Hongbing Wang

Affiliations

Soon will be listed here.

Abstract

Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 (FMR1) gene. Most FXS cases occur due to the expansion of the CGG trinucleotide repeats in the 5' un-translated region of FMR1, which leads to hypermethylation and in turn silences the expression of FMRP (fragile X mental retardation protein). Numerous studies have demonstrated that FMRP interacts with both coding and non-coding RNAs and represses protein synthesis at dendritic and synaptic locations. In the absence of FMRP, the basal protein translation is enhanced and not responsive to neuronal stimulation. The altered protein translation may contribute to functional abnormalities in certain aspects of synaptic plasticity and intracellular signaling triggered by Gq-coupled receptors. This review focuses on the current understanding of FMRP function and potential therapeutic strategies that are mainly based on the manipulation of FMRP targets and knowledge gained from FXS pathophysiology.

Citing Articles

Postnatal downregulation of Fmr1 in microglia promotes microglial reactivity and causes behavioural alterations in female mice.

Hooshmandi M, Ho-Tieng D, Lister K, Cai W, Wong C, Brown N Mol Autism. 2025; 16(1):17.

PMID: 40055803 PMC: 11887208. DOI: 10.1186/s13229-025-00648-2.

Proteomics insights into fragile X syndrome: Unraveling molecular mechanisms and therapeutic avenues.

Abbasi D, Berry-Kravis E, Zhao X, Cologna S Neurobiol Dis. 2024; 194:106486.

PMID: 38548140 PMC: 11650894. DOI: 10.1016/j.nbd.2024.106486.

Ca-stimulated adenylyl cyclases as therapeutic targets for psychiatric and neurodevelopmental disorders.

Chen J, Ding Q, An L, Wang H Front Pharmacol. 2022; 13:949384.

PMID: 36188604 PMC: 9523369. DOI: 10.3389/fphar.2022.949384.

Fragile X Syndrome Caused by Maternal Somatic Mosaicism of Gene: Case Report and Literature Review.

Gomez-Rodriguez M, Morales-Conejo M, Arteche-Lopez A, Sanchez-Calvin M, Quesada-Espinosa J, Gomez-Manjon I Genes (Basel). 2022; 13(9).

PMID: 36140775 PMC: 9498456. DOI: 10.3390/genes13091609.

341 Repeats Is Not Enough for Methylation in a New Fragile X Mouse Model.

Colvin S, Lea N, Zhang Q, Wienisch M, Kaiser T, Aida T eNeuro. 2022; 9(5).

PMID: 35977823 PMC: 9469916. DOI: 10.1523/ENEURO.0142-22.2022.

References

Eberhart D, Malter H, Feng Y, Warren S . The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum Mol Genet. 1996; 5(8):1083-91. DOI: 10.1093/hmg/5.8.1083. View

Darnell J, Klann E . The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci. 2013; 16(11):1530-6. PMC: 3999698. DOI: 10.1038/nn.3379. View

Auerbach B, Osterweil E, Bear M . Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature. 2011; 480(7375):63-8. PMC: 3228874. DOI: 10.1038/nature10658. View

Dolan B, Duron S, Campbell D, Vollrath B, Rao B, Ko H . Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc Natl Acad Sci U S A. 2013; 110(14):5671-6. PMC: 3619302. DOI: 10.1073/pnas.1219383110. View

Strumbos J, Brown M, Kronengold J, Polley D, Kaczmarek L . Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b. J Neurosci. 2010; 30(31):10263-71. PMC: 3485078. DOI: 10.1523/JNEUROSCI.1125-10.2010. View

Weiler I, Irwin S, Klintsova A, Spencer C, Brazelton A, Miyashiro K . Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc Natl Acad Sci U S A. 1997; 94(10):5395-400. PMC: 24689. DOI: 10.1073/pnas.94.10.5395. View

Dobkin C, Rabe A, Dumas R, Idrissi A, Haubenstock H, Brown W . Fmr1 knockout mouse has a distinctive strain-specific learning impairment. Neuroscience. 2000; 100(2):423-9. DOI: 10.1016/s0306-4522(00)00292-x. View

Ronesi J, Collins K, Hays S, Tsai N, Guo W, Birnbaum S . Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci. 2012; 15(3):431-40, S1. PMC: 3288402. DOI: 10.1038/nn.3033. View

Huber K, Gallagher S, Warren S, Bear M . Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A. 2002; 99(11):7746-50. PMC: 124340. DOI: 10.1073/pnas.122205699. View

10.

Berry-Kravis E, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K . Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med. 2012; 4(152):152ra127. DOI: 10.1126/scitranslmed.3004214. View

11.

Leigh M, Nguyen D, Mu Y, Winarni T, Schneider A, Chechi T . A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J Dev Behav Pediatr. 2013; 34(3):147-55. PMC: 3706260. DOI: 10.1097/DBP.0b013e318287cd17. View

12.

Eadie B, Cushman J, Kannangara T, Fanselow M, Christie B . NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice. Hippocampus. 2010; 22(2):241-54. DOI: 10.1002/hipo.20890. View

13.

Deng P, Sojka D, Klyachko V . Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile X syndrome. J Neurosci. 2011; 31(30):10971-82. PMC: 6623101. DOI: 10.1523/JNEUROSCI.2021-11.2011. View

14.

Rong R, Ahn J, Huang H, Nagata E, Kalman D, Kapp J . PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nat Neurosci. 2003; 6(11):1153-61. DOI: 10.1038/nn1134. View

15.

Nalavadi V, Muddashetty R, Gross C, Bassell G . Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation. J Neurosci. 2012; 32(8):2582-7. PMC: 3427762. DOI: 10.1523/JNEUROSCI.5057-11.2012. View

16.

Olmos-Serrano J, Corbin J, Burns M . The GABA(A) receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome. Dev Neurosci. 2011; 33(5):395-403. PMC: 3254038. DOI: 10.1159/000332884. View

17.

Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell I . Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010; 10:91. PMC: 2958860. DOI: 10.1186/1471-2377-10-91. View

18.

Miyashiro K, Beckel-Mitchener A, Purk T, Becker K, Barret T, Liu L . RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron. 2003; 37(3):417-31. DOI: 10.1016/s0896-6273(03)00034-5. View

19.

Corbin F, Bouillon M, Fortin A, Morin S, Rousseau F, Khandjian E . The fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes. Hum Mol Genet. 1997; 6(9):1465-72. DOI: 10.1093/hmg/6.9.1465. View

20.

Michalon A, Sidorov M, Ballard T, Ozmen L, Spooren W, Wettstein J . Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron. 2012; 74(1):49-56. PMC: 8822597. DOI: 10.1016/j.neuron.2012.03.009. View