Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Abstract

Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs). Moreover, small GTPases transduce signals by their downstream effector molecules. Many studies demonstrate that small GTPases of the Ras family are involved in neurodegeneration processes. Here, in this review, we focus on the signaling pathways controlled by these small protein superfamilies that culminate in neurodegenerative pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, we concentrate on the two most studied families of the Ras superfamily: the Ras and Rho families. We summarize the latest findings of small GTPases of the Ras and Rho families in neurodegeneration in order to highlight these small proteins as potential therapeutic targets capable of slowing down different neurodegenerative diseases.

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

“…Rho GTPases are a subfamily of the Ras superfamily proteins and include the key classical proteins RhoA, Rac1, and Cdc42 of the over 20 that have been identified. In addition to critical functions in the nervous system, Rho GTPases regulate cellular behavior such as morphogenesis, survival, proliferation, membrane trafficking, adhesion, and transcriptional activation (Zegers and Friedl, 2014 ; Arrazola Sastre et al, 2020 ; Clayton and Ridley, 2020 ). Rho GTPases are found in all eukaryotic species and are highly conserved which underscores their importance for survival (Hall, 2012 ; Beljan et al, 2020 ).…”

“…Early studies showed that Ras superfamily GTPases control toxic peptides, such as Aβ42 in amyloid plaques and phosphorylated tau of neurofibrillary tangles, via the MAPK pathway (Gärtner et al, 1999 ). They also induce dendritic spine and synapse loss, which are major AD hallmarks, and Ras controls the L-DOPA-induced dyskinesia in PD as well (Arrazola Sastre et al, 2020 ).…”

“…Both ITSN and Cdc42 are essential for neuronal spine development and neuronal survival. ITSN-1 overexpression alters Cdc42-mediated endocytosis, potentially contributing to AD pathology (Arrazola Sastre et al, 2020 ).…”

“…RhoA is the member of the Rho subfamily that is correlated with the formation of actomyosin contractile fibers (Arrazola Sastre et al, 2020 ). Specifically, changes in RhoA localization have been linked to neurodegeneration seen in AD (Huesa et al, 2010 ).…”

Small GTPases of the Rab and Arf Families: Key Regulators of Intracellular Trafficking in Neurodegeneration

“…The GTPase activating proteins (GAPs), on the contrary, are responsible for the inactivation of the GTPase by inducing the intrinsic GTPase activity that results in the hydrolysis of the GTP. Finally, guanine nucleotide dissociation inhibitors (GDIs) prevent the dissociation of the GDP from the GTPase, therefore maintaining the GTPase in an inactive state [ 4 , 5 ]. Moreover, small GTPases can also be regulated by post-translational modifications that permit their binding to either specific proteins or membranes.…”