Ras, RhoA, and vascular pharmacology in neurodevelopment and aging

Abstract

Small GTPases Ras, Rac, and RhoA are crucial regulators of cellular functions. They also act in dysregulated cell proliferation and transformation. Multiple publications have focused on illuminating their roles and mechanisms, including in immune system pathologies. Their functions in neurology-related diseases, neurodegeneration and neurodevelopment, are also emerging, as well as their potential as pharmacological targets in both pathologies. Observations increasingly suggest that these pathologies may relate to activation (or suppression) of signaling by members of the Ras superfamily, especially Ras, Rho, and Rac isoforms, and components of their signaling pathways. Germline (or embryonic) mutations that they harbor are responsible for neurodevelopmental disorders, such as RASopathies, autism spectrum disorder, and dilated cardiomyopathy. In aging, they promote neurodegenerative diseases, with Rho GTPase featuring in their pharmacology, as in the case of Alzheimer's disease (AD). Significantly, drugs with observed anti-AD activity, particularly those involved in cardiovascular systems, are associated with the RhoA signaling, as well as cerebral vasculature in brain development and aging. This leads us to suggest that anti-AD drugs could inform neurodevelopmental disorders, including pediatric low-grade gliomas pharmacology. Neurodevelopmental disorders associated with RhoA, like autism, are also connected with vascular systems, thus could be targets of vascular system-connected drugs.