Jacquemont, S, Pacini, L, Cencelli, G, Jønch, E, Andrea, D, Willemsen, R, Tassone, F, Hagerman, R, Bagni, C, Gasparini, Fabrizio, He, Yunsheng, Rozenberg, Izabela and Gomez-Mancilla, Baltazar (2018) Altered and normal levels of protein synthesis in fragile X syndrome, studies in humans and mice. Science translational medicine, 27 (12). pp. 2039-2051. ISSN 10.1093/hmg/ddy099

Abstract

Fragile X syndrome (FXS) is the most common monogenic form of inherited intellectual disability and
autism spectrum disorder. Two decades of intense basic research on the function of FMRP show that its
absence in FXS causes aberrant signaling leading to upregulated mRNA translation and protein synthesis and
as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies in mice and flies have
shown that several pharmacological interventions can partially or fully restore those deficits and it was
postulated that altered protein synthesis and synaptic architecture mediate the cognitive and behavioral
deficits observed in patients with FXS. This led to one of the most comprehensive drug development
program undertaken thus far for a genetically defined neurodevelopmental disorder but this effort yielded
negative results. Our aim was to characterize the distribution of de novo rates of protein synthesis in patients
with FXS and its relationship with clinical severity. We measured the rate of protein synthesis in fibroblasts
of 32 individuals with FXS, 17 controls as well as in fibroblasts and primary neurons of 30 Fmr1 KO mice,
in two different isogenic backgrounds. Our results show that levels of protein synthesis are clearly increased
in fibroblasts of individuals with fragile X. However, this “cellular phenotype” displays a broad distribution
and a significant proportion of fragile X individuals and fmr1 KO mice have measures in the normal range.
To test the validity of our study conducted in peripheral tissue, we used the fmr1 KO mouse model to show
that measures in fibroblasts predict those in neurons of the same animals. Finally, we show that protein
synthesis but not FMRP explains a significant proportion of the variance in adaptive skills measured in
individuals with FXS. Our study offers a potential explanation for the negative trials and suggests that a
significant proportion, but not all individuals with FXS, may benefit from the reduction of excessive levels
of protein synthesis.

Item Type:	Article
Date Deposited:	19 Jun 2018 00:45
Last Modified:	19 Jun 2018 00:45
URI:	https://oak.novartis.com/id/eprint/33871