Regional rates of brain protein synthesis are unaltered in dexmedetomidine sedated young men with fragile X syndrome: A L-[1-11C]leucine PET study.
Regional rates of brain protein synthesis are unaltered in dexmedetomidine sedated young men with fragile X syndrome: A L-[1-11C]leucine PET study.
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患有脆性 X 综合征的年轻男性接受右美托咪定镇静后，脑部蛋白质合成的区域率没有改变：一项 L-[1-11C]亮氨酸 PET 研究。
DOI：
10.1016/j.nbd.2020.104978
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发表时间：
2020
影响因子：
6.1
通讯作者：
Smith,CarolynBeebe
中科院分区：
文献类型：
--
作者：
Schmidt,KathleenC;Loutaev,Inna;Quezado,Zenaide;Sheeler,Carrie;Smith,CarolynBeebe
脆性X综合征（FXS）是智力残疾最常见的遗传原因。脆性X智力低下蛋白（FMRP），一个假定的翻译抑制因子，在FXS中缺失或显著减少。一个流行的假设是，蛋白质合成的速率增加了这种调节蛋白的缺乏。与这一假设雅阁，我们以前曾报道过FXS的Fmr 1基因敲除小鼠模型的脑蛋白合成（rCPS）速率增加，其他人也报道了海马脑片的类似效应。为了解决人类受试者的假设，我们应用L[1- 11 C]亮氨酸PET方法测量FXS成人和健康对照的rCPS。所有受试者均为男性，年龄在18至24岁之间，未使用精神药物。由于大多数脆性X参与者无法在清醒状态下接受PET研究，我们在成像研究期间使用右美托咪定进行镇静。我们发现，在10名健康对照者中，右美托咪定镇静期间测量的rCPS与清醒状态之间没有差异。在右美托咪定镇静的脆性X参与者（n= 9）和健康对照者（n= 14）的rCPS比较中，我们没有发现统计学显著差异。我们的结果从人的大脑中的vivomeasthenin不支持的假设，rCPS升高，由于缺乏FMRP。这一假说是基于动物模型和体外测量人类外周细胞的结果。翻译抑制子的缺失可能会在调节翻译的途径中产生比以前认为的更复杂的反应。我们可能需要修改我们关于FXS的工作假设和我们对潜在治疗方法的思考。
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 theFmr1knockout 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 fromin vivomeasurements 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 andin vitromeasurements 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.