基因技术探索预防智障

近日，研究人员开发了一种新方法，该方法使动物免受基因中断而导致的智力障碍，其中包括严重的记忆障碍和焦虑。该项研究重点是治疗Syngap1基因突变的影响，该文已经发表在《生物精神病学》杂志上。

“我们希望这些研究最终将专门治疗因Syngap1基因突变造成的精神疾病。” Gavin Rumbaugh博士说，“动物模型显示，发病早期是治疗这种类型遗传障碍的关键时期。”

导致功能蛋白质数量减少的Syngap1基因有害突变是散发性智力障碍的最常见原因之一，并与精神分裂症和孤独症等疾病有关。早期研究表明，这些智力障碍情况在非遗传性基因突变中占2-8%。散发性智力障碍影响约占全球人口的百分之一，该结果表明成千上万的智力障碍患者可能在不知情的情况下携带Syngap1基因有害突变。

在新的研究中，研究人员在动物发育过程中检测到了Syngap1基因突变的影响，发现基因突变破坏关键时期神经元的生长，这个关键时期是指小鼠出生后一到三周的时间内。“我们发现，某些类型的皮层神经元在发育早期生长非常快，然后导致早产儿形成某种类型的神经回路。”Massimilano Aceti博士说。

“致病性Syngap1突变基因对引导新生皮质电路的锥体细胞突触后结构动力学和结构完整性产生深远影响，”研究者说。“这些研究结果支持这样的设想，即中断树突细胞生长和脊柱可塑性的关键时期可能是大脑发育障碍的一个常见的病理过程”。

研究人员推断，这个过程可能会对大脑连通性造成永久性错误影响，他们可能会通过在新生突变小鼠中加强Syngap1蛋白来阻止这些影响。事实上，他们发现在成年突变小鼠体内有个子神经元被错接，这表明神经元的早期增长可能导致终身神经回路连接问题。然而研究人员发现，利用先进的基因技术提高新生突变小鼠Syngap1蛋白质含量，只有在关键发育期开始前这种策略才能完全保护小鼠。

Rumbaugh博士和他的同事正在研发一种筛查程序来寻找一种可能恢复缺陷神经元中Syngap1蛋白质含量的药物类化合物。他们希望随着个性化医疗的进步,最终能根据患者基因型来确定最适合患者的疗法。（转化医学网360zhyx.com）

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原文：Researchers at the Florida campus of The Scripps Research Institute (TSRI) say they have produced an approach that protects animal models against a type of genetic disruption that causes intellectual disability, including serious memory impairments and altered anxiety levels. The study (“Syngap1 Haploinsufficiency Damages a Postnatal Critical Period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly”), which focuses on treating the effects of mutations to the Syngap1 gene, have been published online in Biological Psychiatry ahead of print.
"Our hope is that these studies will eventually lead to a therapy specifically designed for patients with psychiatric disorders caused by damaging Syngap1 mutations," said Gavin Rumbaugh, Ph.D., a TSRI associate professor who led the study. "Our model shows that the early developmental period is the critical time to treat this type of genetic disorder."
Damaging mutations in Syngap1 that reduce the number of functional proteins are one of the most common causes of sporadic intellectual disability and are associated with schizophrenia and autism spectrum disorder. Early estimates suggest that these non-inherited genetic mutations account for two to eight percent of these intellectual disability cases. Sporadic intellectual disability affects approximately one percent of the worldwide population, suggesting that tens of thousands of individuals with intellectual disability may carry damaging Syngap1 mutations without knowing it.
In the new study, the researchers examined the effect of damaging Syngap1 mutations during development and found that the mutations disrupt a critical period of neuronal growth: a period between the first and third postnatal weeks in mouse models. "We found that a certain type of cortical neuron grows too quickly in early development, which then leads to the premature formation of certain types of neural circuits," said research associate Massimilano Aceti, Ph.D., first author of the study.
“Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits,” wrote the investigators. “These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.”
The researchers reasoned that this process might cause permanent errors in brain connectivity and that they might be able to head off these effects by enhancing the Syngap1 protein in the newborn mutant mice. Indeed, they found that a subset of neurons were misconnected in the adult mutant mice, suggesting that early growth of neurons can lead to life-long neural circuit connectivity problems. Then, using advanced genetic techniques to raise Syngap1 protein levels in newborn mutant mice, the researchers found this strategy completely protected the mice only when the approach was started before this critical developmental window opened.
As a result of these studies, Dr. Rumbaugh and his colleagues are now developing a drug-screening program to look for drug-like compounds that could restore levels of Syngap1 protein in defective neurons. They hope that, as personalized medicine advances, such a therapy could ultimately be tailored to patients based on their genotype.