Cogram Patricia, Fernández-Beltrán Luis C, Casarejos María José, Sánchez-Yepes Sonia, Rodríguez-Martín Eulalia, García-Rubia Alfonso, Sánchez-Barrena María José, Gil Carmen, Martínez Ana, Mansilla Alicia
Department of Genetics, Institute of Ecology and Biodiversity (IEB), Faculty of Sciences, Universidad de Chile, Santiago, Chile.
FRAXA-DVI, FRAXA Research Foundation, Santiago, Chile.
Front Neurosci. 2022 Nov 16;16:1007531. doi: 10.3389/fnins.2022.1007531. eCollection 2022.
Fragile X syndrome (FXS) is caused by the loss of function of Fragile X mental retardation protein (FMRP). FXS is one of the leading monogenic causes of intellectual disability (ID) and autism. Although it is caused by the failure of a single gene, FMRP that functions as an RNA binding protein affects a large number of genes secondarily. All these genes represent hundreds of potential targets and different mechanisms that account for multiple pathological features, thereby hampering the search for effective treatments. In this scenario, it seems desirable to reorient therapies toward more general approaches. Neuronal calcium sensor 1 (NCS-1), through its interaction with the guanine-exchange factor Ric8a, regulates the number of synapses and the probability of the release of a neurotransmitter, the two neuronal features that are altered in FXS and other neurodevelopmental disorders. Inhibitors of the NCS-1/Ric8a complex have been shown to be effective in restoring abnormally high synapse numbers as well as improving associative learning in FMRP mutant flies. Here, we demonstrate that phenothiazine FD44, an NCS-1/Ric8a inhibitor, has strong inhibition ability and sufficient bioavailability in the mouse brain. More importantly, administration of FD44 to two different FXS mouse models restores well-known FXS phenotypes, such as hyperactivity, associative learning, aggressive behavior, stereotype, or impaired social approach. It has been suggested that dopamine (DA) may play a relevant role in the behavior and in neurodevelopmental disorders in general. We have measured DA and its metabolites in different brain regions, finding a higher metabolic rate in the limbic area, which is also restored with FD44 treatment. Therefore, in addition to confirming that the NCS-1/Ric8a complex is an excellent therapeutic target, we demonstrate the rescue effect of its inhibitor on the behavior of cognitive and autistic FXS mice and show DA metabolism as a FXS biochemical disease marker.
脆性X综合征（FXS）由脆性X智力低下蛋白（FMRP）功能丧失引起。FXS是导致智力残疾（ID）和自闭症的主要单基因病因之一。尽管它由单个基因功能缺陷所致，但作为RNA结合蛋白的FMRP会继发影响大量基因。所有这些基因代表了数百个潜在靶点以及导致多种病理特征的不同机制，从而阻碍了有效治疗方法的探寻。在这种情况下，将治疗方法转向更通用的途径似乎是可取的。神经元钙传感器1（NCS-1）通过与鸟嘌呤交换因子Ric8a相互作用，调节突触数量和神经递质释放概率，这两个神经元特征在FXS和其他神经发育障碍中会发生改变。NCS-1/Ric8a复合物抑制剂已被证明可有效恢复异常高的突触数量，并改善FMRP突变果蝇的联想学习能力。在此，我们证明吩噻嗪FD44作为一种NCS-1/Ric8a抑制剂，在小鼠脑中具有强大的抑制能力和足够的生物利用度。更重要的是，将FD44给予两种不同的FXS小鼠模型可恢复众所周知的FXS表型，如多动、联想学习、攻击行为、刻板行为或社交接近障碍。有人提出多巴胺（DA）可能在行为以及一般神经发育障碍中发挥相关作用。我们测量了不同脑区的DA及其代谢产物，发现边缘区域的代谢率较高，FD44治疗也可使其恢复。因此，除了证实NCS-1/Ric8a复合物是一个极佳的治疗靶点外，我们还证明了其抑制剂对认知和自闭症FXS小鼠行为的挽救作用，并表明DA代谢是FXS的一种生化疾病标志物。
