Regional rates of brain protein synthesis are unaltered in dexmedetomidine sedated young men with fragile X syndrome: A L-[1-11C]leucine PET study

• Published in: Neurobiology of disease Vol. 143; p. 104978
• Main Authors: Schmidt, Kathleen C., Loutaev, Inna, Quezado, Zenaide, Sheeler, Carrie, Smith, Carolyn Beebe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2020; Elsevier
• Subjects: Adolescent; Brain - drug effects; Brain - metabolism; Carbon Radioisotopes; Dexmedetomidine; Dexmedetomidine - pharmacology; Fragile X syndrome; Fragile X Syndrome - metabolism; Humans; Hypnotics and Sedatives - pharmacology; Leucine; Male; Positron emission tomography; Positron-Emission Tomography - methods; Protein Biosynthesis - drug effects; Protein Biosynthesis - physiology; Protein synthesis; Sedation; Translation; Young Adult; Translation; Protein synthesis; Dexmedetomidine; Fragile X syndrome; Sedation; Leucine; Positron emission tomography
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2020.104978

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein (FMRP), a putative translation suppressor, is absent or significantly reduced in FXS. One prevailing hypothesis is that rates of protein synthesis are increased by the absence of this regulatory protein. In accord with this hypothesis, we have previously reported increased rates of cerebral protein synthesis (rCPS) in the Fmr1 knockout mouse model of FXS and others have reported similar effects in hippocampal slices. To address the hypothesis in human subjects, we applied the L[1-11C]leucine PET method to measure rCPS in adults with FXS and healthy controls. All subjects were males between the ages of 18 and 24 years and free of psychotropic medication. As most fragile X participants were not able to undergo the PET study awake, we used dexmedetomidine for sedation during the imaging studies. We found no differences between rCPS measured during dexmedetomidine-sedation and the awake state in ten healthy controls. In the comparison of rCPS in dexmedetomidine-sedated fragile X participants (n = 9) and healthy controls (n = 14) we found no statistically significant differences. Our results from in vivo measurements in human brain do not support the hypothesis that rCPS are elevated due to the absence of FMRP. This hypothesis is based on findings in animal models and in vitro measurements in human peripheral cells. The absence of a translation suppressor may produce a more complex response in pathways regulating translation than previously thought. We may need to revise our working hypotheses regarding FXS and our thinking about potential therapeutics. •Brain protein synthesis rate unaffected under dexmedetomidine sedation in young men.•Brain protein synthesis rates not higher in sedated fragile X men than healthy controls.•Absence of FMRP may have complex effects on protein synthesis.