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

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 apparatus, hallmarks that have been related to both Rab and Arf GTPases functions. Despite their relationship with neurodegenerative disorders, very few studies have focused on the role of these GTPases in the pathogenesis of neurodegeneration. In this review, we summarize their importance in the onset and progression of Alzheimer's and Parkinson's diseases, as well as their emergence as potential therapeutical targets for neurodegeneration.

Keywords: Alzheimer; Arf GTPase; Parkinson; Rab GTPase; membrane trafficking; neurodegeneration; small GTPase; transport; vesicle.

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 their effector molecules. Rab GTPases can interact with coat proteins, motor proteins, tethering proteins and SNAREs; Arf GTPases interact with coat proteins and adaptors. This results in the control of vesicle transport and membrane trafficking. The cycle culminates by the inactivation of the GTPase by GTPase activating proteins (GAP). G: guanosine.

Figure 2

Scheme of the signalling pathways controlled by the small guanosine triphosphatases (GTPases) of the Rab family that are dysregulated in Alzheimer’s disease (AD) (purple), in Parkinson’s disease (PD) (blue) or in both (yellow). Silencing Rab1 induces Golgi fragmentation, while Rab1 overexpression can rescue it in both diseases. Rab1-regulated ER to GA traffic is inhibited by α-syn in PD. α-syn also alters Rab1A/Atg9 axis and consequently reduces the autophagosome formation. Regarding Rab5, its overactivation could alter the axonal transport of growth signals in AD. In PD, α-synuclein (α-syn) overexpression results in an activation of Rab5, which in turn interacts with dynein and dysregulates the axonal transport. Rab5 also participates in amyloid precursor protein (APP) processing, as well as in amyloid-β (Aβ) clearance in coordination with Rab7. This Aβ internalization by Rab5/Rab7 is considered as neuroprotective according to some studies, whereas it is considered as neurotoxic according to others. Rab7 favors the clearance of α-syn aggregates. LRRK2G2019S alters the endocytosis rate, which can be reverted by constitutively active Rab7 overexpression. Parkin ubiquitinates Rab7 and regulates vesicle transport via the Rab7/Rab-interacting lysosomal protein (RILP) axis. βCTF: β-cleavage C-terminal fragments; ER: endoplasmic reticulum; GA: Golgi apparatus; NFT: neurofibrillary tangle; NGF: nerve growth factor.

Figure 3

Scheme of the signalling pathways controlled by the small guanosine triphosphatases (GTPases) of the Arf family that are dysregulated in Alzheimer’s disease (AD) (purple) and Parkinson’s disease (PD) (blue). In AD, signalling pathways controlled by Arf are involved in amyloid precursor protein (APP) trafficking to plasma membrane and amyloid-β (Aβ) species secretion. Arf also controls Aβ species levels by favouring the proteasomal degradation of β-site APP cleaving enzyme 1 (BACE1). Arl8 blocks neurodegeneration mediated by Aβ. Regarding PD, ArfGAP1 silencing blocks the neurite retraction induced by LRRK2G2019S. sAPP: soluble APP; GGA3: Golgi-localized γ-ear containing Arf-binding protein 3.