Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer's Disease

Abstract

Rab GTPases (Rabs) are small proteins that play crucial roles in vesicle transport and membrane trafficking. Owing to their widespread functions in several steps of vesicle trafficking, Rabs have been implicated in the pathogenesis of several disorders, including cancer, diabetes, and multiple neurodegenerative diseases. As treatments for neurodegenerative conditions are currently rather limited, the identification and validation of novel therapeutic targets, such as Rabs, is of great importance. This review summarises proof-of-concept studies, demonstrating that modulation of Rab GTPases in the context of Alzheimer's disease (AD) can ameliorate disease-related phenotypes, and provides an overview of the current state of the art for the pharmacological targeting of Rabs. Finally, we also discuss the barriers and challenges of therapeutically targeting these small proteins in humans, especially in the context of AD.

Keywords: Alzheimer’s; Rab GTPases; neurodegeneration.

Figure 1

The Intracellular pathways and a selected number of Rab GTPases associated with the endoplasmic reticulum (ER), Golgi, trans-Golgi network (TGN), and endosomal pathways. Rab1 and Rab2 are localised to the ER and Golgi, and play a role in the ER to Golgi apparatus trafficking pathway, via the endoplasmic reticulum to Golgi intermediate compartment (ERGIC). Rab3 is localised to synaptic secretory vesicles (SV) and the plasma membrane and is involved in exocytosis and neurotransmitter release. Rab4 has a role in protein recycling and transport to the plasma membrane and is localised to early endosomes (EE). Rab5 is localised to the EE and aids its fusion and formation. Rab6 is involved with regulating intra-Golgi trafficking. Rab7 is localised to the late endosome (LE), lysosome (L), and autophagosomes (AP) and is involved in the maturation and transport between these vesicles. Rab8 is associated with exocytosis from the TGN to the plasma membrane, with localisation to the plasma membrane and SV. Rab10 is localised to the ER, Golgi, endosomes, and GLUT4 vesicles and is involved in ER dynamics, endocytosis, and trafficking to the plasma membrane. Rab11 is also localised to the Golgi, as well as the recycling endosome (RE) and EE. Rab13 is involved in the TGN and RE to plasma membrane transport pathway. Rab19 has been shown to localise to the Golgi, however there is little known about its role. Rab27 is involved in exocytosis, localising to SV. Rab29 and Rab39 are both localised to the Golgi. Rab32 localises to the ER and mitochondria, with a role in mitochondrial dynamics and autophagy. Rab35 localises to the plasma membrane, and is involved in endocytic recycling. Rabs more strongly associated with secretory pathways are shaded in blue while those more strongly associated with endosomal pathways are shown in red. Adapted with permission from Hutagalung et al. 2022, American Physiological Society [7].

Figure 2

The cycle of Rab GTPase activation. Newly synthesised de novo Rab GTPases interact with Rab escort protein (REP), which enables prenylation via geranylgeranyltransferase (GGTase). When active, Rab GTPases are bound to GTP and associated with their target membrane. Following hydrolysis of GTP to GDP, they become inactive and reside in the cytosol. The Rab GTPase activation cycle is aided by a number of effectors. GTPase activating proteins (GAPs) catalyse the hydrolysis of GTP to GDP to inactivate the Rab. GDP dissociation inhibitors (GDIs) retrieve the inactive Rab from the membrane and solubilises it in the cytosol. However, guanine exchange factors (GEFs) catalyse the exchange of GDP with GTP, thus reactivating the Rab [12].

Figure 3

Rab-mediated amyloid precursor protein metabolism. De novo amyloid precursor protein (APP) is produced with the endoplasmic reticulum (ER) and transported to Golgi for protein maturation via a Rab1 trafficking pathway. Upon passage through the Golgi and trans-Golgi network (TGN), APP resides with the plasma membranes. APP may be processed via the non-amyloidogenic route via α-secretase producing soluble APPα which is released into the extracellular environment. Alternatively, APP along with β-secretases may be internalised via Rab5-dependent endocytosis. Once in the acidic internal compartments of early and late endosomes (EE/LE) the cleavage of APP via β-secretases generates the β-C-terminal fragment (β-CTF). β-secretases is in turn recycled to the plasma membrane either directly via Rab4-mediated traffic, via recycling endosomes (RE) dependent on Rab11 trafficking or trafficking alongside the β-CTF to the Golgi. Within the Golgi and TGN, the γ-secretase complex facilitated by its association with Rab6 processes the β-CTF into β-amyloid (Aβ) which is trafficking into secretary vesicles via Rab10 and released via Rab27/Rab3-dependent process, alongside post Golgi trafficking APP and β-secretase. Also shown is the faciliatory role of Ras and Rab interactor 3 (RIN3) and adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) on Rab5-mediated endocytosis as well as the association of GDP dissociation inhibitors (GDIα/β) with the γ-secretase component presenilin-1. The alternative processing of β-CTF into Aβ within the lysosomes is not shown in this schematic. Rabs more strongly associated with secretory pathways are shaded in blue while those more strongly associated with endosomal pathways are shown in red.