小柯机器人

美国南加州大学Giorgia Quadrato课题组近日取得一项新成果。经过不懈努力，他们的研究揭示了自闭症谱系障碍（ASD）相关基因SYNGAP1在大脑皮层神经中的非突触功能。相关论文发表在2023年11月9日出版的《自然-神经科学》杂志上。

研究人员发现突触Ras GTPase-activating(RASGAP)蛋白1（SYNGAP1，ASD的顶级风险基因）在人类放射胶质细胞（hRGCs）的顶端结构域中表达。在SYNGAP1单倍体缺失的人类皮质类器官模型中，研究发现细胞骨架动力学失调损害了hRGCs的支架和分裂平面，导致皮质投射神经元的分层紊乱和成熟加速。

此外，研究还证实，在Syngap1单倍体缺失小鼠模型中，祖细胞与神经元的比例失调。因此，SYNGAP1相关脑部疾病可能是通过非突触机制产生的，这凸显了在人类不同细胞类型和发育阶段研究与神经发育障碍（NDDs）相关基因的必要性。

据悉，自闭症谱系障碍相关罕见遗传变异中富含与突触功能有关的基因。研究表明皮层神经发生失调是ASD病理生理学中的一种趋同现象，但目前仍不清楚"突触"ASD风险基因如何导致这些在突触发生前就已出现的表型。

附：英文原文

Title: Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis

Author: Birtele, Marcella, Del Dosso, Ashley, Xu, Tiantian, Nguyen, Tuan, Wilkinson, Brent, Hosseini, Negar, Nguyen, Sarah, Urenda, Jean-Paul, Knight, Gavin, Rojas, Camilo, Flores, Ilse, Atamian, Alexander, Moore, Roger, Sharma, Ritin, Pirrotte, Patrick, Ashton, Randolph S., Huang, Eric J., Rumbaugh, Gavin, Coba, Marcelo P., Quadrato, Giorgia

Issue&Volume: 2023-11-09

Abstract: Genes involved in synaptic function are enriched among those with autism spectrum disorder (ASD)-associated rare genetic variants. Dysregulated cortical neurogenesis has been implicated as a convergent mechanism in ASD pathophysiology, yet it remains unknown how ‘synaptic’ ASD risk genes contribute to these phenotypes, which arise before synaptogenesis. Here, we show that the synaptic Ras GTPase-activating (RASGAP) protein 1 (SYNGAP1, a top ASD risk gene) is expressed within the apical domain of human radial glia cells (hRGCs). In a human cortical organoid model of SYNGAP1 haploinsufficiency, we find dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination and accelerated maturation of cortical projection neurons. Additionally, we confirmed an imbalance in the ratio of progenitors to neurons in a mouse model of Syngap1 haploinsufficiency. Thus, SYNGAP1-related brain disorders may arise through non-synaptic mechanisms, highlighting the need to study genes associated with neurodevelopmental disorders (NDDs) in diverse human cell types and developmental stages. Experiments in human cortical organoid and mouse models of SYNGAP1 haploinsufficiency, which is associated with autism spectrum disorder (ASD), reveal altered cortical neurogenesis, suggesting that a non-synaptic mechanism contributes to the disorder.

DOI: 10.1038/s41593-023-01477-3

Source: https://www.nature.com/articles/s41593-023-01477-3

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex