Association of lipid rafts cholesterol with clinical profile in fragile X syndrome

Amanda Toupin,François Corbin,Artuela Çaku,Thamàs Fülöp,Asma Laroui,Luc Galarneau,Armita Abolghasemi,Sérine Benachenhou

doi:10.1038/s41598-022-07064-z

Abstract

Fragile X syndrome (FXS) is the most prevalent monogenic cause of intellectual disability and autism spectrum disorder (ASD). Affected individuals have a high prevalence of hypocholesterolemia, however, the underlying mechanisms and the clinical significance remains unknown. We hypothesized that decrease in the plasma cholesterol levels is associated with an alteration of cholesterol content within the lipid rafts (LRs) which ultimately affects the clinical profile of FXS individuals. The platelets LRs were isolated by ultracentrifugation on sucrose gradient from 27 FXS and 25 healthy controls, followed by measurements of proteins, cholesterol, and gangliosides content. Autistic and adaptive behaviour of affected individuals were respectively assessed by the Social Communication Questionnaire and Adaptive Behavior Assessment System. Our results suggest a decrease in the cholesterol content of LRs in FXS individuals as compared to controls. As opposed to controls, LR cholesterol was significantly associated with plasma total cholesterol (r = 0.47; p = 0.042) in the FXS group. Furthermore, the correlation between LRs cholesterol and the clinical profile showed a significant association with autistic traits (r = − 0.67; p < 0.001) and adaptative behavior (r = 0.70; p < 0.001). These results support the clinical significance of LR cholesterol alterations in FXS. Further studies are warranted to investigate the implication of LRs in FXS pathophysiology and ASD.

Highlights

Fragile X Syndrome (FXS), an X-linked neurodevelopmental disorder, is the most prevalent monogenic cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD)[1]
The present study reports the first investigation of Lipid rafts (LRs) from platelets of Fragile X syndrome (FXS) participants as compared to healthy controls
Our data show a slight reduction of LRs cholesterol in FXS as compared to healthy controls

Summary

Introduction

Fragile X Syndrome (FXS), an X-linked neurodevelopmental disorder, is the most prevalent monogenic cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD)[1]. Lipid rafts (LRs) are dynamic structures enriched in cholesterol, proteins, and gangliosides that transiently move within the plasma membrane in order to facilitate a cellular r esponse[11]. These platforms recruit important synaptic receptors including mGluRs, NMDAR, and AMPAR12. Since cholesterol is essential for cell membrane integrity, synaptic development and neurotransmitter release, a decrease of plasma cholesterol could alter the content in cholesterol of LRs and potentially contribute to the FXS physiopathology[23,24]. FMRP levels quantified in the platelets of the FXS affected individuals are lower than those observed in the healthy controls and significantly correlate with cognitive functions[29]

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