Stress-Sensitive Protein Rac1 and Its Involvement in Neurodevelopmental Disorders

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.

Figure 1

Regulation and interaction of Rac1-related signaling pathways at the postsynaptic terminal. Effectors of FXS and Huntington's disease, such as FMRP and HTT, can directly activate or inhibit Rac1 activity to modulate its downstream signaling cascades, mainly via the Rac1-PAK-cofilin pathway, which subsequently influences synaptic plasticity. In schizophrenia, NMDA receptors activate Kal-7 via TIAM1, while DISC1 and NRG1/ErbB4 interact with Kal-7 to activate or inhibit Rac1. In ASD, SHANK3 directly modulates Rac1 activity, while other effectors like AUTS2, P-Rex-1, and Elmo2/Dock180 form a complex to modulate Rac1 activity and then affect NMDA receptor activity through the PAK pathway. In Rett syndrome, BDNF activates TrkB receptors to modulate the activity of CDKL5 and MECP2 that further regulate the function of the Rac1-cofilin pathway. Abnormalities of these proteins in any pathways may affect neuroplasticity and cause neurodevelopmental disorders.

Figure 2

Putative schematic of the Rac1 signaling pathways involved in different neurodevelopmental disorders. The upstream effector, such as Kal-7, AUTS2, NMDAR, or FMRP, activates or inhibits Rac1 activity to modulate its downstream signaling cascades, primarily via the PAK-cofilin pathway, which orchestrates neuronal cell migration, spinogenesis, and synaptic plasticity. Abnormalities in this Rac1-related signaling complex are common features of neurodevelopmental disorders. The dashed lines indicate certain mechanisms that remain unclear and require further investigation.