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.

Keywords: Alzheimer; Cdc42; Keywords: GTPases; Parkinson; Rac; Rap; Ras; Rho; neurodegeneration.

Figure 1

Activation/deactivation cycle of small guanosine triphosphatases (GTPases). The input receiving cells mediate GEF activation, facilitating the transition from the inactive configuration (guanosine-5′-diphosphate (GDP)-loaded, in red) to the active configuration (GTP-loaded, in green). In the active form, small GTPases interact with effector molecules in order to transduce signals that generate different cellular responses. On the other hand, GAPs promote the hydrolysis of GTP and the consequent inactivation of the GTPase. GEF: guanine nucleotide exchange factor. GAP: GTPase activating protein.

Figure 2

Scheme of the signaling pathways controlled by small GTPases of the Ras family, which are deregulated in general (yellow), in Alzheimer’s disease (AD) (purple), and Parkinson’s disease (PD) (blue) in neurodegenerative diseases. (A) Signaling pathways controlled by Ras GTPase in neurons and microglia. Growth factor receptor-bound protein 2 (Grb2)/SOS-1/Ras/ mitogen-activated protein kinase (MAPK), decreased RasGRF1/Ras, Ras/afadin-6 (AF-6), and Ras/RIN1 promote different responses that induce neurodegeneration. Ras/Tiam1 and Ras/PI3K in neurons, and Ras/extracellular signal-regulated kinase (ERK) in microglia, which could be altered in neurodegenerative diseases. (B) Signaling cascade controlled by Rap GTPases in neurons. Rap1/MAPK and PDZ-GEF1/Rap2/c-Jun N-terminal kinase (JNK) favor neurodegenerative processes. Rap1-induced miR-124 inhibition increases the production of toxic amyloid-β (Aβ). PDE6δ controls Rap1/MAPK pools that are driving to neurodegenerative responses. However, Rap1/STEF/Rac1 is inducing a protective phenotype. (C) Signaling axis controlled by Rheb GTPase. Rheb/mTOR can or cannot drive neurodegeneration depending of the input in neurons. Furthermore, reduced Rheb protein levels provoke a reduction in BACE1 degradation, which induces the generation of Aβ species.

Figure 3

Scheme of the signaling pathways controlled by small GTPases of the Rho family, which are deregulated in general (yellow), in AD (purple), and PD (blue) in neurodegenerative diseases. (A) RhoA GTPase signaling pathways in neurons and microglia. RhoA/ROCK controls SRF–SRE gene transcription in neurons. In microglia, RhoA is activated via α-Synuclein (α-syn)/CD11B/RhoA and AT1/RhoA. (B) Signaling axis controlled by Rac1 GTPase in neurons, astrocytes, and microglia. In neurons, Tiam1/Rac1, Rac1/NOX1, and Rac1/JNK are inducing neurodegeneration, whereas the Rac1/PAK axis can drive neurodegeneration according to the input. Rac1 also decreases α-syn accumulation. In astrocytes, ITGβ1/PI3K/cPKC/Rac1 is leading to neurodegeneration, promoting astrogliosis by an increase of its gene expression targets and reactive oxygen species (ROS) generation. In microglia, the Vav/Rac1 axis is affecting neuronal viability by both, generating ROS and phagocytosis activation. On the other hand, Rac1/WAVE is decreasing Aβ_1–42 levels by activating phagocytosis. (C) Signaling cascade controlled by Cdc42 GTPase in neurons. The axes intersectin (ITSN)/Cdc42 and Cdc42/GSK-3β, together with RhoA and Rac1, are driving to neurodegenerative responses.