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首页> 外文期刊>Platelets >Platelets as a surrogate disease model of neurodevelopmental disorders: Insights from Fragile X Syndrome
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Platelets as a surrogate disease model of neurodevelopmental disorders: Insights from Fragile X Syndrome

机译：血小板作为神经发育障碍的替代疾病模型：脆弱X综合征的见解

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Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism spectrum disorders (ASD). Despite a large number of therapeutics developed in past years, there is currently no targeted treatment approved for FXS. In fact, translation of the positive and very promising preclinical findings from animal models to human subjects has so far fallen short owing in part to the low predictive validity of the Fmr1 ko mouse, an overly simplistic model of the complex human disease. This issue stresses the critical need to identify new surrogate human peripheral cell models of FXS, which may in fact allow for the identification of novel and more efficient therapies. Of all described models, blood platelets appear to be one of the most promising and appropriate disease models of FXS, in part owing to their close biochemical similarities with neurons. Noteworthy, they also recapitulate some of FXS neuron's core molecular dysregulations, such as hyperactivity of the MAPK/ERK and PI3K/Akt/mTOR pathways, elevated enzymatic activity of MMP9 and decreased production of cAMP. Platelets might therefore help furthering our understanding of FXS pathophysiology and might also lead to the identification of disease-specific biomarkers, as was shown in several psychiatric disorders such as schizophrenia and Alzheimer's disease. Moreover, there is additional evidence suggesting that platelet signaling may assist with prediction of cognitive phenotype and could represent a potent readout of drug efficacy in clinical trials. Globally, given the neurobiological overlap between different forms of intellectual disability, platelets may be a valuable window to access the molecular underpinnings of ASD and other neurodevelopmental disorders (NDD) sharing similar synaptic plasticity defects with FXS. Platelets are indeed an attractive model for unraveling pathophysiological mechanisms involved in NDD as well as to search for diagnostic and therapeutic biomarkers.
机译：脆弱的X综合征（FXS）是最常见的智力障碍的遗传形式和自闭症谱系障碍（ASD）的主要单身原因。尽管在过去几年开发了大量的治疗方法，但目前没有针对FXS批准的有针对性的待遇。事实上，从动物模型到人类受试者的阳性和非常有前途的临床前发现的翻译已经短缺，部分归因于FMR1 KO小鼠的低预测有效性，这是复杂人类疾病的过度简单的模型。这个问题强调了识别FXS的新代理人外周细胞模型的危急需要，实际上可能允许鉴定新颖和更有效的疗法。在所有描述的模型中，血小板似乎是FXS最有前途和适当的疾病模型之一，部分原因是它们与神经元的密切生化相似之处。值得注意的是，他们还重新承载了一些FXS神经元的核心分子缺陷，如MAPK / ERK和PI3K / AKT / MTOR途径的多动，MMP9的酶活性升高，营地的生产降低。因此，血小板可能有助于进一步了解对FXS病理生理学的理解，并且也可能导致鉴定特异性疾病的生物标志物，如若干精神病疾病如精神分裂症和阿尔茨海默病。此外，还有额外的证据表明血小板信号可以有助于预测认知表型，并且可以代表临床试验中药物功效的有效读数。在全球范围内，鉴于不同形式的智力残疾之间的神经生物学重叠，血小板可以是获得ASD和其他神经发育疾病（NDD）的分子下限的有价值的窗口，与FXS共用类似的突触可塑性缺陷。血小板确实是用于解开涉及NDD的病理生理机制的有吸引力的模型，以及寻找诊断和治疗生物标志物。

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