RhoA Signaling in Neurodegenerative Diseases

Abstract

Ras homolog gene family member A (RhoA) is a small GTPase of the Rho family involved in regulating multiple signal transduction pathways that influence a diverse range of cellular functions. RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells. Indeed, emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we summarize the current knowledge of RhoA regulation and downstream cellular functions with an emphasis on the role of RhoA signaling in neurodegenerative diseases and the therapeutic potential of RhoA inhibition in neurodegeneration.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; Ras homolog gene family member A (RhoA); Rho-associated coiled-coil-containing kinase (ROCK); amyotrophic lateral sclerosis.

Figure 1

RhoA protein domains and 3D structure. (A) The RHOA gene is located on the short arm of chromosome 3 (3p21.3). (B) RhoA is a monomeric protein comprised of 193 amino acids and a molecular mass of 21.7 kDa. The different domains and their amino acid positions are marked. The G-domain responsible for nucleotide binding contains five motifs, G1–G5, where the G2 and G3 motifs are located in the switch I and II regions that change conformation in response to GTP/GDP binding. The insert domain and the hypervariable C-terminus are involved in regulatory or effector protein binding, while the CAAX motif in the C-terminal end undergoes post-translational lipid modification crucial for membrane targeting. (C) 3D structure and conformation of the RhoA–GDP complex and the RhoA–GTP complex. Marked in blue is the P-loop (G1 motif) that binds the β,γ-phosphate of the guanine nucleotide and a Mg²⁺ ion. Marked in red are the switch I and II regions responsible for the conformational change of the protein in response to GTP/GDP binding.

Figure 2

RhoA regulation. (A) RhoA cycle between an active GTP-bound conformation at the plasma membrane and an inactive GDP-bound conformation in the cytosol facilitated by prenylation and different regulatory proteins: guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), guanine nucleotide dissociation inhibitors (GDIs), and GDI displacement factors (GDFs).(B) Post-translational modification events mapped onto the amino acid sequence of RhoA with highlighted locations of the functional protein domains from Figure 1. (C) Transcriptional and post-transcriptional regulation of RhoA showing known transcription factors and miRNAs regulating RHOA transcription.

Figure 3

RhoA signaling. RhoA transmits signals from a variety of different cell surface receptors, such as integrins, tyrosine kinase receptors, G protein-coupled receptors, and cytokine receptors, by interacting with downstream effector molecules involved in many cellular processes. These include, Golgi function, gene transcription, inflammation, autophagy, cell death, cytoskeletal modulation, mitochondrial homeostasis, and cytokinesis.