Hospital Israelita Albert Einstein, São Paulo, Brazil.
Departamento de Genética e Biologia Evolutiva, Instituto de Biociência, Universidade de São Paulo, São Paulo, Brazil.
Sci Rep. 2018 Jul 24;8(1):11138. doi: 10.1038/s41598-018-29309-6.
Several lines of indirect evidence, such as mutations or dysregulated expression of genes related to cytoskeleton, have suggested that cytoskeletal dynamics, a process essential for axons and dendrites development, is compromised in autism spectrum disorders (ASD). However, no study has yet examined whether cytoskeleton dynamics is functionally altered in cells from ASD patients. Here we investigated the regulation of actin cytoskeleton dynamics in stem cells from human exfoliated deciduous teeth (SHEDs) of 13 ASD patients and 8 control individuals by inducing actin filament depolymerization and then measuing their reconstruction upon activation of the RhoGTPases Rac, Cdc42 or RhoA. We observed that stem cells from seven ASD individuals (53%) presented altered dymanics of filament reconstruction, including a patient recently studied by our group whose iPSC-derived neuronal cells show shorten and less arborized neurites. We also report potentially pathogenic genetic variants that might be related to the alterations in actin repolymerization dynamics observed in some patient-derived cells. Our results suggest that, at least for a subgroup of ASD patients, the dynamics of actin polymerization is impaired, which might be ultimately leading to neuronal abnormalities.
有几条间接证据表明，细胞骨架相关基因的突变或表达失调，表明细胞骨架动力学（轴突和树突发育所必需的过程）在自闭症谱系障碍（ASD）中受到损害。然而，尚无研究检测 ASD 患者的细胞中细胞骨架动力学是否发生了功能改变。在这里，我们通过诱导肌动蛋白丝解聚来研究来自 13 名 ASD 患者和 8 名对照个体的人脱落乳牙（SHED）中的干细胞中的肌动蛋白细胞骨架动力学的调节，然后在激活 Rac、Cdc42 或 RhoA 时测量它们的重建。我们观察到，来自七个 ASD 个体（53%）的干细胞的丝状重建动力学发生了改变，包括我们小组最近研究的一名患者，其 iPSC 衍生的神经元细胞显示出缩短和较少分支的神经突。我们还报告了潜在的致病性遗传变异，这些变异可能与一些患者来源的细胞中观察到的肌动蛋白重新聚合动力学改变有关。我们的结果表明，至少对于 ASD 患者的一个亚组，肌动蛋白聚合的动力学受损，这可能最终导致神经元异常。
