Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy.
Department of Engineering, University of Palermo, Viale delle Scienze Ed. 8, 90128 Palermo, Italy.
Int J Mol Sci. 2021 Jun 7;22(11):6167. doi: 10.3390/ijms22116167.
Intellectual disability (ID) is a pathological condition characterized by limited intellectual functioning and adaptive behaviors. It affects 1-3% of the worldwide population, and no pharmacological therapies are currently available. More than 1000 genes have been found mutated in ID patients pointing out that, despite the common phenotype, the genetic bases are highly heterogeneous and apparently unrelated. Bibliomic analysis reveals that ID genes converge onto a few biological modules, including cytoskeleton dynamics, whose regulation depends on Rho GTPases transduction. Genetic variants exert their effects at different levels in a hierarchical arrangement, starting from the molecular level and moving toward higher levels of organization, i.e., cell compartment and functions, circuits, cognition, and behavior. Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype. Systems biology (SB) approaches are more focused on the overall interconnected network rather than on individual genes, thus encouraging the design of therapies that aim to correct common dysregulated biological processes. This review summarizes current knowledge about cytoskeleton control in neurons and its relevance for the ID pathogenesis, exploiting in silico modeling and translating the implications of those findings into biomedical research.
智力障碍（ID）是一种以智力功能有限和适应行为障碍为特征的病理状况。它影响全球 1-3%的人口，目前尚无药物治疗方法。在 ID 患者中发现了 1000 多个突变基因，这表明尽管表型相同，但遗传基础高度异质，且显然无关。文献分析表明，ID 基因集中在几个生物学模块上，包括细胞骨架动力学，其调节依赖于 Rho GTPases 的转导。遗传变异在一个层次结构中的不同水平发挥作用，从分子水平开始，一直到更高的组织水平，即细胞区室和功能、回路、认知和行为。因此，对细胞过程（如神经元迁移、神经突生成和突触可塑性）有影响的细胞骨架改变会影响有效网络的整体建立，并因此影响认知表型。系统生物学（SB）方法更侧重于整体相互连接的网络，而不是单个基因，从而鼓励设计旨在纠正常见失调生物过程的治疗方法。本综述总结了目前关于神经元细胞骨架控制及其与 ID 发病机制相关性的知识，利用计算机建模并将这些发现的意义转化为生物医学研究。
