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

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State: Public
Version: Final published version
Serval ID
serval:BIB_B39C9DDE6F71
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Protein synthesis levels are increased in a subset of individuals with fragile X syndrome.
Journal
Human molecular genetics
Author(s)
Jacquemont S., Pacini L., Jønch A.E., Cencelli G., Rozenberg I., He Y., D'Andrea L., Pedini G., Eldeeb M., Willemsen R., Gasparini F., Tassone F., Hagerman R., Gomez-Mancilla B., Bagni C.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Publication state
Published
Issued date
15/06/2018
Peer-reviewed
Oui
Volume
27
Number
12
Pages
2039-2051
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absence of the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNA translation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here, we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical severity. We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here, we show that levels of protein synthesis are increased in fibroblasts of individuals with FXS and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those in neurons we suggest the validity of this peripheral biomarker. Our study offers a potential explanation for the comprehensive drug development program undertaken thus far yielding negative results and suggests that a significant proportion, but not all individuals with FXS, may benefit from the reduction of excessive levels of protein synthesis.
Keywords
Adolescent, Adult, Aged, Animals, Autism Spectrum Disorder/genetics, Autism Spectrum Disorder/physiopathology, Child, Disease Models, Animal, Female, Fibroblasts/metabolism, Fibroblasts/pathology, Fragile X Mental Retardation Protein/biosynthesis, Fragile X Mental Retardation Protein/genetics, Fragile X Syndrome/genetics, Fragile X Syndrome/physiopathology, Hippocampus/metabolism, Hippocampus/physiopathology, Humans, Male, Mice, Mice, Knockout, Middle Aged, Neurons/metabolism, Neurons/pathology, Young Adult
Pubmed
Web of science
Open Access
Yes
Create date
29/03/2018 16:40
Last modification date
20/08/2019 15:22
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