Stress-Sensitive Protein Rac1 and Its Involvement in Neurodevelopmental Disorders.

Xiaohui Wang,Linjie Li,Guan Wang,Shuli Zhang,Xuefeng Wang,Yue Li,Fangzhen Wei,Dongbin Liu,Lei Zhang,Fushun Wang

doi:10.1155/2020/8894372

Abstract

Ras-related C3 botulinum toxin substrate 1 (Rac1) is a small GTPase that is well known for its sensitivity to the environmental stress of a cell or an organism. It senses the external signals which are transmitted from membrane-bound receptors and induces downstream signaling cascades to exert its physiological functions. Rac1 is an important regulator of a variety of cellular processes, such as cytoskeletal organization, generation of oxidative products, and gene expression. In particular, Rac1 has a significant influence on certain brain functions like neuronal migration, synaptic plasticity, and memory formation via regulation of actin dynamics in neurons. Abnormal Rac1 expression and activity have been observed in multiple neurological diseases. Here, we review recent findings to delineate the role of Rac1 signaling in neurodevelopmental disorders associated with abnormal spine morphology, synaptogenesis, and synaptic plasticity. Moreover, certain novel inhibitors of Rac1 and related pathways are discussed as potential avenues toward future treatment for these diseases.

Highlights

As a member of the Ras-homologous (Rho) small GTPase family, related C3 botulinum toxin substrate 1 (Rac1) is well known for its versatility in mediating the response of cells or organisms when facing external disturbances or environmental challenges, such as heat shock [1], oxidative stress [2], mechanical stress [3], genotoxic stress [4], hypoxic stress [5], or even higher-level mental stress from social confrontation and fear [6,7,8,9]
It is commonly accepted that Rac1 and related signaling pathways are prominently involved in the maintenance and regulation of basic nervous system functions including neurite outgrowth, neuronal migration, synaptogenesis, synaptic plasticity, and learning memory [10,11,12,13]
The dysregulation of Rac1 has been indicated in the processes of neuronal morphogenesis, migration, and synaptic plasticity in neurodevelopmental disorders such as schizophrenia, Autism spectrum disorders (ASD), and Fragile X syndrome (FXS), as highlighted in the review

Summary

Introduction

As a member of the Ras-homologous (Rho) small GTPase family, Rac is well known for its versatility in mediating the response of cells or organisms when facing external disturbances or environmental challenges, such as heat shock [1], oxidative stress [2], mechanical stress [3], genotoxic stress [4], hypoxic stress [5], or even higher-level mental stress from social confrontation and fear [6,7,8,9]. Rac has gained increased attention in the field of neuroscience with its roles in brain structure and function becoming more widely appreciated. It is commonly accepted that Rac and related signaling pathways are prominently involved in the maintenance and regulation of basic nervous system functions including neurite outgrowth, neuronal migration, synaptogenesis, synaptic plasticity, and learning memory [10,11,12,13]. Not until recently have studies revealed that Rac may be relevant for certain inherited neurodevelopmental disorders, likely due to its essential role in the regulation of neuronal cell structure and development [15,16,17,18,19]. We aim Neural Plasticity to sketch a picture of the newly identified roles of Rac in these diseases and to shed light on the potential of specific inhibitors for Rac as novel therapeutics

Basic Molecular Mechanism of Rac1 Signaling

Rac1 and Neurodevelopmental Disorders

Conclusions

Conflicts of Interest