International Journal of Molecular Sciences Review Small GTPases of the Rab and Arf Families: Key Regulators of Intracellular Trafficking in Neurodegeneration Alazne Arrazola Sastre 1,2, Miriam Luque Montoro 1, Hadriano M. Lacerda 3, Francisco Llavero 1,4,* and José L. Zugaza 1,2,5,* 1 Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, 48940 Leioa, Spain; [email protected] (A.A.S.); [email protected] (M.L.M.) 2 Department of Genetics, Physical Anthropology and Animal Physiology, University of Basque Country UPV/EHU, 48940 Leioa, Spain 3 Three R Labs, Science Park of the UPV/EHU, 48940 Leioa, Spain; [email protected] 4 Hospital 12 de Octubre Research Institute (i+12), 28041 Madrid, Spain 5 IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain * Correspondence: [email protected] (F.L.); [email protected] (J.L.Z.) Abstract: Small guanosine triphosphatases (GTPases) of the Rab and Arf families are key regulators of vesicle formation and membrane trafficking. Membrane transport plays an important role in the central nervous system. In this regard, neurons require a constant flow of membranes for the correct distribution of receptors, for the precise composition of proteins and organelles in dendrites and axons, for the continuous exocytosis/endocytosis of synaptic vesicles and for the elimination of dysfunctional proteins. Thus, it is not surprising that Rab and Arf GTPases have been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Both pathologies share characteristics such as the presence of protein aggregates and/or the fragmentation of the Golgi Citation: Arrazola Sastre, A.; Luque apparatus, hallmarks that have been related to both Rab and Arf GTPases functions. Despite their Montoro, M.; Lacerda, H.M.; Llavero, relationship with neurodegenerative disorders, very few studies have focused on the role of these F.; Zugaza, J.L. Small GTPases of the GTPases in the pathogenesis of neurodegeneration. In this review, we summarize their importance Rab and Arf Families: Key Regulators in the onset and progression of Alzheimer’s and Parkinson’s diseases, as well as their emergence as of Intracellular Trafficking in Neurodegeneration. Int. J. Mol. Sci. potential therapeutical targets for neurodegeneration. 2021, 22, 4425. https://doi.org/ 10.3390/ijms22094425 Keywords: Rab GTPase; Arf GTPase; small GTPase; Alzheimer; Parkinson; neurodegeneration; membrane trafficking; vesicle; transport Academic Editor: Giuseppe Lazzarino Received: 29 March 2021 Accepted: 20 April 2021 1. Introduction Published: 23 April 2021 Eukaryotic cells constantly receive information from the extracellular medium by the binding of growth factors, hormones, peptides, and ions to specific receptors. This binding Publisher’s Note: MDPI stays neutral triggers the transmission of a message through signaling cascades in the cytoplasm to with regard to jurisdictional claims in induce a precise biological response [1]. One of the central elements responsible for the published maps and institutional affil- diffusion of this message are the small guanosine triphosphatases (GTPases) of the Ras iations. superfamily. These small GTPases participate in signaling cascades that control a wide range of cell responses, such as proliferation, differentiation and apoptosis [2,3]. The small GTPases are molecular switches that can be found in two states: an inac- tive state in which the small GTPase is bound to GDP, and an active state in which it is Copyright: © 2021 by the authors. bound to GTP. The process by which the GTPase changes from the inactive to the active Licensee MDPI, Basel, Switzerland. state is known as the GTPase activation cycle. Three main molecules control the activa- This article is an open access article tion/deactivation cycle. The guanine exchange factors (GEFs) are in charge of activating distributed under the terms and the GTPase by favoring the release of GDP and the binding of GTP. The GTPase activating conditions of the Creative Commons proteins (GAPs), on the contrary, are responsible for the inactivation of the GTPase by Attribution (CC BY) license (https:// inducing the intrinsic GTPase activity that results in the hydrolysis of the GTP. Finally, creativecommons.org/licenses/by/ guanine nucleotide dissociation inhibitors (GDIs) prevent the dissociation of the GDP from 4.0/). Int. J. Mol. Sci. 2021, 22, 4425. https://doi.org/10.3390/ijms22094425 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 4425 2 of 24 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 24 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 toGTPase either by specific inducing proteins the intrinsic or membranes.GTPase activity Thus, that results they in can the be hy farnesylated,drolysis of the GTP. geranylgerany- latedFinally, or guanine palmitoylated nucleotide in dissociation their C-terminal inhibitors region (GDIs) andprevent myristoylated the dissociation in of their the N-terminal regionGDP from [5,6 ].the GTPase, therefore maintaining the GTPase in an inactive state [4,5]. Moreover,The Ras small superfamily GTPases can of also small be regulated GTPases by is dividedpost-translat intoional five modifications families: Ras, that Rho, Rab, Arf, permit their binding to either specific proteins or membranes. Thus, they can be and Ran [2,3]. The Ras family is specialized in the control of cell growth and metabolism. farnesylated, geranylgeranylated or palmitoylated in their C-terminal region and Additionally,myristoylated in Ras their family N-terminal GTPases region cooperate [5,6]. with the Rho family to regulate the cell cycle, geneThe expression Ras superfamily and cell of transformation.small GTPases is divided Apart into from five those families: functions, Ras, Rho, the Rab, Rho family of GTPasesArf, and Ran are responsible[2,3]. The Ras for family the actin is specialized cytoskeleton in the organization, control of cell whereas growth theandRab and the Arfmetabolism. families Additionally, control the Ras intracellular family GTPases traffic co ofoperate vesicles with andthe Rho membranes family to regulate and the formation andthe cell intracellular cycle, genetransport expression of and vesicles, cell transformation. respectively. Apart Last, from the GTPasesthose functions, of the the Ran family are inRho charge family of of the GTPases nucleocytoplasmic are responsible for transport the actin [ 2cytoskeleton,3,5,7]. organization, whereas the RabMost and of the the Arf intracellular families control compartments, the intracellularsuch traffic as of thevesicles nucleus, and membranes mitochondria or the and the formation and intracellular transport of vesicles, respectively. Last, the GTPases Golgiof the Ran apparatus family are (GA), in charge are separated of the nucleocytoplasmic by membranes. transport Thus, [2,3,5,7] eukaryotic. cells require specific mechanismsMost of the for intracellular the traffic betweencompartment theses, such organelles. as the nucleus, Furthermore, mitochondria coordinated or the membrane traffickingGolgi apparatus between (GA), are different separated cell by types membranes. is needed Thus, in eukaryotic multicellular cells require organisms specific [ 8]. The Rab GTPases,mechanisms the for largest the traffic family between of the these Ras organelles. superfamily, Furthermore, are key coordinated regulators membrane of vesicle sorting and membranetrafficking between trafficking. different They cell cantypes control is needed this in traffic multicellular by interacting organisms with [8]. The effector Rab molecules suchGTPase ass, the the coat largest proteins family (COPI, of the Ras COPII, superfamily, and clathrin), are key motor regulators proteins of vesicle (kinesins sorting and dyneins), tetheringand membrane complexes trafficking. (early They endosome can control antigen this 1 traffic (EEA1), by Golgins,interacting exocyst with effector and the homotypic molecules such as the coat proteins (COPI, COPII, and clathrin), motor proteins (kinesins fusionand dyneins), and protein tethering sorting complexes (HOPS) (early complex), endosome andantigen SNAREs 1 (EEA1 [8),]. Golgins, Conversely, exocyst Arf GTPases participateand the homotypic in vesicle fusion formation, and protein especially sorting ( inHOPS the) GAcomplex), [9], but and they SNAREs are also[8]. present in theConversely, plasma Arf membrane, GTPases part endosomesicipate in vesicle and lipid formation, droplets especially [9]. To in regulate the GA [9] vesicle, but formation, likethey Rab,are also the present Arf GTPases in the plasma interact membrane, with effector endosomes molecules and lipid such droplets as the [9] coat. To proteins and theirregulate adaptors vesicle formation, (COPI, Golgi-localized like Rab, the Arf GTPasesγ-ear containing interact with Arf-binding effector molecules proteins such (GGA), and Munc18-interactingas the coat proteins andproteins their adaptors (MINT)). (COPI, Therefore, Golgi-localized the γ Rab-ear containing and Arf familiesArf-bind- of GTPases regulateing proteins the (GGA endomembranes), and Munc18-interacting system (Figure proteins1). (MINT)). Therefore, the Rab and Arf families of GTPases regulate the endomembranes system (Figure 1). Figure 1. Rab and Arf GTPases and their role in membrane trafficking. Rab and Arf GTPases are activated by guanine exchange factors (GEF). Once activated, they interact with