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Review

Consequences of Rab GTPase dysfunction in genetic or acquired human diseases

Marcellus J. BanworthDepartment of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAView further author information
&
Guangpu LiDepartment of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USACorrespondence[email protected]
View further author information
Pages 158-181 | Received 10 Jan 2017, Accepted 24 Oct 2017, Published online: 28 Dec 2017

ABSTRACT

Rab GTPases are important regulators of intracellular membrane trafficking in eukaryotes. Both activating and inactivating mutations in Rab genes have been identified and implicated in human diseases ranging from neurological disorders to cancer. In addition, altered Rab expression is often associated with disease prognosis. As such, the study of diseases associated with Rabs or Rab-interacting proteins has shed light on the important role of intracellular membrane trafficking in disease etiology. In this review, we cover recent advances in the field with an emphasis on cellular mechanisms.

Introduction

Intracellular membrane trafficking is key to cell metabolism and survival. In order to maintain cellular homeostasis, vesicular transport of membranes and proteins to proper organelles in the cell is essential. In this regard, Rab GTPases are central regulators of vesicular transport, and they represent the largest branch of the Ras-related monomeric GTPase superfamily [Citation1–5]. There are 66 Rab genes in the human genome [Citation6]. Each Rab regulates multiple events at a specific organelle during vesicular transport, including vesicle formation [Citation7–10], vesicle movement along the cytoskeleton [Citation11–21], and vesicle tethering/docking/fusion with a target compartment [Citation22–27] along endocytic and exocytic pathways ().

Figure 1. Subcellular localization of mammalian Rab GTPases and disease implications. Each Rab specifically targets and localizes to a membrane compartment along the exocytic and endocytic pathways in the cell as indicated. At steady state, each Rab may be found on multiple related organelles, based on and references therein. The association of Rab31 with exocrine granules is based on our unpublished immunohistochemistry data showing Rab31 localization to mucin granules of goblet cells in human and mouse intestinal epithelium. Early endosomes, recycling endosomes and secretory vesicles represent heterogeneous populations of vesicles, and the associated Rabs do not necessarily co-localize on the same vesicles. Also indicated are examples of diseases associated with several Rabs.

Figure 1. Subcellular localization of mammalian Rab GTPases and disease implications. Each Rab specifically targets and localizes to a membrane compartment along the exocytic and endocytic pathways in the cell as indicated. At steady state, each Rab may be found on multiple related organelles, based on Table 1 and references therein. The association of Rab31 with exocrine granules is based on our unpublished immunohistochemistry data showing Rab31 localization to mucin granules of goblet cells in human and mouse intestinal epithelium. Early endosomes, recycling endosomes and secretory vesicles represent heterogeneous populations of vesicles, and the associated Rabs do not necessarily co-localize on the same vesicles. Also indicated are examples of diseases associated with several Rabs.

Each Rab is localized to the cytoplasmic surface of a particular membrane compartment or transport vesicle [Citation28–31], and the Rab membrane association requires post-translational isoprenylation (geranylgeranylation) of one or two cysteine residues at or near the C-terminus [Citation32]. Like other GTPases, Rabs function by alternating between active GTP-bound and inactive GDP-bound conformations, with the GTP-bound form interacting with a wide range of effector proteins and promoting multiple steps in vesicular transport. The Rab effectors include cargo proteins to be sorted during vesicle formation, motor proteins for vesicle movement, and tethering factors for vesicle fusion. A single Rab can interact with multiple effectors temporally and spatially. For example, Rab5 has been shown to bind to multiple effectors of different functions in a GTP-dependent fashion in effector pull-down assays, which includes the tethering factor EEA1 and the guanine nucleotide exchange factor (GEF) complex Rabaptin-5/Rabex-5 [Citation33]. The Rab GTPase cycle is facilitated by regulators such as GEFs and GTPase-activating proteins (GAPs) in the cell to accelerate GDP dissociation and GTP hydrolysis [Citation34,Citation35], respectively, since the intrinsic rates are usually very low. The GTPase cycle is coupled with the membrane association and dissociation cycle, which is facilitated by the GDP dissociation inhibitor (GDI) [Citation36,Citation37]. GDI removes inactive GDP-bound Rab from the target membranes and recycles it back to the donor membranes for re-activation and a new round of Rab function in vesicular transport (). While current data are consistent with this model of Rab GTPase cycle, the model should be interpreted with caution in the sense that it is not fully established, especially in the areas of membrane targeting specificity and GDI-mediated recycling in the cell.

Figure 2. Rab GTPase cycle, Rab-interacting proteins and disease implications. Each newly synthesized Rab initially binds to REP-1, which recruits the α and β subunits of the Rab GGTase for post-translational isoprenylation. The prenylated Rab remains complexed with REP-1 and is targeted to the membrane where a cognate GEF facilitates the nucleotide exchange of GDP for GTP and thereby activates the Rab. The GTP-bound Rab can interact with multiple effector proteins temporally and spatially to promote vesicle formation, movement and fusion. Each Rab associates with a particular type of vesicles and interacts with a specific set of effectors, e.g. Rab5 associates with early endosomes and one of its effectors is APPL1 for signaling on endosomes while Rab27 associates with melanosomes and its effectors include Melanophilin and Myosin Va for movement on actin. Upon membrane tethering and docking, the Rab reaches the target membrane to facilitate SNARE-mediated membrane fusion after which a cognate GAP facilitates GTP hydrolysis and converts the Rab to inactive GDP-bound conformation. The GDP-bound Rab is extracted by GDI and delivered back to the donor membrane for a new round of action. Several diseases are known to be associated with the regulators and effectors of the Rab GTPase cycle as indicated.

Figure 2. Rab GTPase cycle, Rab-interacting proteins and disease implications. Each newly synthesized Rab initially binds to REP-1, which recruits the α and β subunits of the Rab GGTase for post-translational isoprenylation. The prenylated Rab remains complexed with REP-1 and is targeted to the membrane where a cognate GEF facilitates the nucleotide exchange of GDP for GTP and thereby activates the Rab. The GTP-bound Rab can interact with multiple effector proteins temporally and spatially to promote vesicle formation, movement and fusion. Each Rab associates with a particular type of vesicles and interacts with a specific set of effectors, e.g. Rab5 associates with early endosomes and one of its effectors is APPL1 for signaling on endosomes while Rab27 associates with melanosomes and its effectors include Melanophilin and Myosin Va for movement on actin. Upon membrane tethering and docking, the Rab reaches the target membrane to facilitate SNARE-mediated membrane fusion after which a cognate GAP facilitates GTP hydrolysis and converts the Rab to inactive GDP-bound conformation. The GDP-bound Rab is extracted by GDI and delivered back to the donor membrane for a new round of action. Several diseases are known to be associated with the regulators and effectors of the Rab GTPase cycle as indicated.

With such a prominent role in membrane trafficking and cell homeostasis, Rabs or Rab-interacting proteins are associated with a multitude of inherited genetic disorders and acquired diseases ranging from neurological diseases to cancer. Depending on the transport pathways, many Rabs have been implicated in various diseases as summarized in and references therein. Here we discuss genetic and acquired diseases associated with Rab mutations or altered expression levels in that order, updating and complementing several previous reviews on the theme [Citation38–40].

Table 1. Rab Functions and Disease Implications.

Charcot-Marie-Tooth Type 2B

Charcot-Marie-Tooth Type 2B (CMT2B) is a hereditary autosomal dominant motor and sensory neuropathy. It represents a subgroup of Charcot-Marie-Tooth (CMT) disease that affects one in every 2,500 individuals and is the most common inherited neurological disease [Citation41]. Phenotypic analyses of CMT2B patients indicate that this disease is an axonal form of peripheral neuropathy characterized by the loss of somatosensory and motor function, which leads to common foot encumbrances such as ulcers and infections with onset of the disease at the age of 20s to 30s [Citation42]. CMT2B is genetically linked to five missense mutations in the RAB7A gene (L129F, K157N, N161I, N161T, V162M) [Citation41,Citation42]. The N161I mutation was the latest addition in 2013 and was the first report of CMT2B in the Asian ethnicity [Citation43]. Because of the later discovery of another Rab7 isoform, Rab7b [Citation44–46], it should be noted that Rab7 in the CMT2B literature refers only to the original isoform (now named Rab7a). Despite the sequence homology and late endosomal localization, Rab7b exhibits different function from Rab7a and promotes transport from late endosomes to the TGN rather than to the lysosome [Citation44,Citation45], which makes it unlikely to compensate for the Rab7a deficiency in CMT2B.

Rab7a localizes to late endosomes and controls late endosome fusion and biogenesis of lysosomes [Citation30,Citation47,Citation48]. Rab7a coordinates with Rab5 in conversion of Rab5-positive early endosomes to Rab7a-positive late endosomes during endosome maturation [Citation49] and has been implicated in multiple cellular functions including apoptosis, neurite growth, and phagocytosis [Citation48]. Interestingly, Rab7a is ubiquitously expressed in all tissues, but the aforementioned Rab7a mutations cause phenotypic consequences only in neuronal cell types, specifically those of the peripheral nervous system [Citation38,Citation50].

Structurally, the five Rab7a missense mutations reside in loops 8 and 10 that coordinate the orientation of guanine base in the bound GTP or GDP molecule [Citation51-53]. Biochemical analyses of these Rab7a missense mutants indicate faster nucleotide exchange rate, leading to constitutive active GTP-bound state due to higher GTP concentration than that of GDP in the cell [Citation51–53]. Along this line, the Rab7a mutants are shown to migrate into the axon and promote premature degradation of neurotrophin receptors, thereby blocking neurotrophin-mediated retrograde signaling from the axon terminal to the soma [Citation54]. With increased Rab7a activity contributing to the phenotypic and morphological attributes of CMT2B, there has been research into the development of Rab7a inhibitors in order to possibly alleviate this neurological disorder. In this regard, one compound (ML282) in the Molecular Libraries Small Molecule Repository (MLSMR) has been found to be proficient inhibitor of Rab7 with higher efficacy towards Rab7a than other Rabs [Citation55]. More recently, however, a loss of Rab7a function appears to be the reason for neurodegeneration in a Drosophila model, and overexpression of the CMT2B Rab7a mutants can actually rescue the neuropathy-like phenotype in a dosage-dependent fashion [Citation56]. This suggests that the CMT2B mutations are loss-of-function mutations rather than gain-of-function mutations as previously thought. If confirmed in humans, a therapeutic approach opposite to the current one would be needed to increase Rab7a function instead.

Warburg Micro syndrome

Warburg Micro syndrome is an autosomal recessive neurological and developmental disorder with phenotypic defects in brain and eye development as well as progressive neurological deterioration in children, which is caused by loss-of-function mutations in Rab18 or the Rab18 GEF (Rab3GAP complex) in about 50% of the cases [Citation57–59]. It is yet to be determined whether the remaining 50% cases of Warburg Micro syndrome are also associated with Rab18 function due to mutations in Rab18 effectors or other factors involved in the Rab18 pathway. While the exact cellular function of Rab18 is unclear, recent studies indicate its localization to the ER and function in maintenance of ER structure [Citation58]. Knockdown of Rab18 by RNAi results in expansion of ER sheets from the perinuclear region towards cell periphery in Hela cells, so does the knockdown of the Rab3GAP complex [Citation58]. Although the Rab3GAP complex was originally discovered and purified for its GAP activity towards Rab3 [Citation60], it was recently found to contain Rab18 GEF activity. This Rab18 GEF activity was abolished by the Rab3GAP mutations (e.g., Rab3GAP1:T18P or E24V and Rab3GAP2:R426C) in Warburg Micro syndrome [Citation58]. Consistently these Rab18 and Rab3GAP mutations produce the same clinical manifestation in brain and eye abnormalities including postnatal microcephaly, developmental delay, congenital bilateral cataracts, microphthalmia and microcornea [Citation57,Citation59].

Carpenter syndrome

Carpenter syndrome is an autosomal recessive neurological disorder of craniosynostosis and limb malformation and is associated with loss-of-function mutations in Rab23 including nonsense and missense mutations [Citation61]. Rab23 is highly expressed in the brain and neurons [Citation62] and is localized to the plasma membrane and early endosomes [Citation63]. Rab23 is shown to regulate the sorting and function of signaling molecules involved in the Sonic Hedgehog signal transduction pathway [Citation64]. Indeed, Rab23 regulates Sonic Hedgehog signaling through controlling the transport and turnover of Hedgehog-associated transmembrane receptor Smoothened in the cilium, which suggests a role in cilia function [Citation65]. Furthermore, the mouse open brain (opb) gene is mapped to Rab23 and blocks Sonic Hedgehog signaling [Citation64]. The opb mutation is a nonsense mutation in Rab23 that leads to premature translation termination and loss of Rab23 function with the phenotype of open neural tube and embryonic lethality [Citation64].

Griscelli Syndrome

Claude Griscelli first described Griscelli Syndrome (GS) in 1978 by characterizing a novel pigment condition paired with immunodeficiency [Citation66]. GS is an autosomal recessive disease characterized by pigment dilution in the hair and skin of patients and by misregulated T lymphocyte and macrophage activation that causes hemophagocytic syndrome [Citation67,Citation68]. The pigment dilution and partial albinism is caused by defective melanosome transport in melanocytes [Citation69,Citation70]. Currently three types of GS are associated with mutations in three different genes, which include MYO5A (GS type 1), RAB27A (GS type 2) and MELANOPHILIN (GS type 3) [Citation71].

It is important to note that Rab27 facilitates melanosome movement and transport along actin cytoskeleton in melanocytes by recruitment of Melanophilin and Myosin Va to the membrane of melanosomes to form a tripartite complex [Citation13,Citation72], which correlates with the mutations of the three genes in the three types of GS. Rab27 has two isoforms (Rab27a and Rab27b) that share 71% amino acid identity. Interestingly, only mutations in the Rab27a gene, which is located on chromosome 15, cause the GS phenotype [Citation73], and these mutations include W73G, L130P, and A152P that inactivate Rab27a and block granule secretion in cytotoxic T lymphocytes [Citation67,Citation68]. In melanocytes, they block melanosome capture by the cortical actin network at the cell periphery and cause melanosome accumulation in the perinuclear region of the cell [Citation69,Citation70,Citation74].

GS is not currently curable. In some cases, hematopoietic stem cell transplantation has been used to rescue the immunodeficiency seen in GS patients, but the defect in melanosome transport remains uncorrected [Citation75]. The ashen mice contain inactivating mutations in Rab27a and constitute an animal model for GS type 2 [Citation73,Citation76]. Transgenic expression of Rab27b in ashen mice can compensate for the Rab27a deficiency and rescue melanosome transport in melanocytes [Citation73], which suggests some degree of functional redundancy between Rab27a and Rab27b and is consistent with the observation that Rab27b is up-regulated in GS type 2 patients [Citation77].

X-linked intellectual disability

X-linked Intellectual Disability (XLID) is a synaptopathy-like disorder caused by mutations in a group of genes on the X chromosome, which mostly encode proteins involved in synaptic plasticity and function [Citation78]. In this regard, one form of XLID is attributed to loss-of-function mutations in Rab39b [Citation79]. Rab39b is expressed in brain neurons and localized to the Golgi complex and endosomes, and inhibition of Rab39b function by shRNA can lead to decreased number of growth cones at the neuronal terminal and synapse formation [Citation79]. Another form of XLID is caused by loss-of-function mutations including both nonsense and missense mutations in a GDI isoform, GDI1 [Citation80,Citation81]. GDI1 encodes GDI-α which is predominantly expressed in the brain. The missense mutant protein (L92P) shows defects in interaction with the synaptic vesicle-associated Rab3a [Citation81,Citation82], and possibly other brain-specific Rabs such as Rab39b, which contributes to the development of XLID.

Choroideremia

Choroideremia (CHM) is an X-linked recessive eye disease that is caused by inactivating mutations in the Rab Escort Protein-1 (REP1) gene [Citation83]. CHM is another example of diseases associated with dysfunction of a Rab regulator or effector, like the aforementioned Melanophilin and Myosin Va in GS. Although CHM is rare only affecting one in 100,000 individuals, this disease develops quickly, and people afflicted exhibit early night blindness by teenage years, which is followed by gradual visual field loss and common blindness by middle age [Citation83]. It is worth noting that CHM is commonly misinterpreted as retinitis pigmentosa or other retinal degeneration diseases, because of similar clinical symptoms [Citation84]. In addition, most females with the mutation are carriers with no symptoms due to the X-linked phylogenetic properties of this gene mutation.

REP1 facilitates the Rab GGTase (geranylgeranyl transferase) reaction by binding to newly synthesized Rab proteins and bringing them into proximity with the catalytic enzyme for post-translational isoprenylation at either one or two cysteine residues located at or near the C terminus of the Rabs [Citation85]. REP1 then delivers the lipid-modified Rabs to each membrane compartment, and the hydrophobicity of the prenyl lipid group anchors the Rabs to the membrane. In CHM, REP1 is non-functional because of inactivating mutations or truncations in the gene sequence [Citation83]. This dysfunction of REP1 causes mislocalization and loss of function of Rab proteins. Through analysis of Rab membrane targeting in lymphocytes, it was discovered that the lack of REP1 expression associated with CHM reduced prenylation of multiple Rabs, and REP2 was shown to compensate for the absence of REP1 and recover the prenylation of several Rabs but not Rab27a [Citation85]. Furthermore, Rab27a is highly expressed in retinal pigment epithelium and choroidal capillaries, in support of the contention that defective Rab27a prenylation is a potential cause of CHM [Citation86]. However, it is worth noting that Rab27a is expressed in multiple tissues and cell types other than retina, e.g., melanocytes and platelets [Citation87], but CHM patients show no clinical defects in these tissues or cell types. Along this line, the aforementioned GS type 2 disease, which is caused by loss-of-function Rab27a mutations, has no known retinal defects suggesting that the REP1 mutations in CHM affects more than Rab27a to induce the retinal degeneration phenotype.

Currently there is no effective treatment for CHM besides symptom management. Recently it has been shown that a significant portion of REP1 non-functional mutations are caused by nonsense mutations, which has led to the development of drugs such as Ataluren (Translarna) to be used as potential counteractive treatments [Citation88]. Retinal gene therapy via recombinant adenoviruses, adeno-associated viruses (AAV) or lentiviruses has also shown promise as another potential avenue for treatment of CHM [Citation89–91]. Importantly, in a 6-patient clinical trial over 6 months, the subretinal delivery of normal REP1 gene via an AAV vector significantly improved the patients' visual acuity and retinal sensitivity [Citation90].

Cancer

Most Rabs show altered expression levels in all cancers except for myeloma based on cancer microarray analysis [Citation92] (). More recently, activating mutations in Rabs have also been identified in human tumor sequencing database, e.g., the A151T and F161L mutations in Rab35 [Citation93]. Like similar mutations in K-Ras, the Rab35 mutants can activate phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) that are essential for cancer cell survival. Along this line, Rab35 is shown to be necessary for growth factor-mediated phosphorylation and activation of AKT in HeLa cells [Citation93]. Rab35 is an endocytic/recycling Rab associated with endosomes and plasma membrane [Citation94,Citation95] and may contribute to growth factor-mediated activation of PI3K/AKT pathway by regulation of endocytosis and recycling, as shown by the endocytosis of PDGFRα driven by the constitutively active Rab35:Q67L mutant [Citation93]. In addition to the activating mutations, increased Rab35 activity can also be achieved by up-regulation of gene expression, which is reported to associate with the onset of ovarian cancer [Citation96]. Interestingly, Rab35 is also shown to interact with p53-related protein kinase (PRPK) in a GTP-dependent manner and suppresses PRPK-induced p53 expression [Citation97]. The p53 protein is a well-known tumor suppressor and down-regulation of p53 is expected to promote tumor cell development by bypassing apoptosis checkpoints.

Altered Rab expression is a common theme in cancer, especially endocytic and recycling Rabs that recycle cell adhesion proteins for cell surface remodeling and are expected to facilitate cell movement and metastasis [Citation10,Citation98–102]. The early endosomal Rabs, such as Rab5 and Rab21, are known to interact with the tails of α subunits of β1 integrins and promote their endocytosis and remodeling at the cell surface, which modulate cell adhesion and migration of breast and prostate cancer cells (MDA-MB-231 and PC3) [Citation10]. Along this line, ablation of Rab5 or Rab21 in carcinoma-associated fibroblasts decreases integrin at the plasma membrane and abrogates the remodeling of extracellular matrix necessary for squamous cell carcinoma invasion [Citation100]. Consistently, Rab5 is over-expressed in highly proliferative and metastatic cancer cells [Citation99,Citation103] while Rab5 activity is suppressed during cell differentiation [Citation104]. Recently, another early endosome-associated Rab (Rab22) was reported to promote microvesicle formation and breast cancer invasion and metastasis and is up-regulated by hypoxia-inducible factors (HIFs), which are often associated with increased risk of metastasis and patient mortality [Citation105]. Along this line, Rab31 (a.k.a. Rab22b) is up-regulated in brain, skin, salivary gland, pancreas, kidney, and gastric cancers but down-regulated in leukemia, lung and colon cancers [Citation38]. Rab31 is highly homologous to Rab22 but targets to TGN instead of early endosomes, and regulates the transport of cargo proteins such as the mannose-6-phosphate receptor (M6PR) to endosomes [Citation106,Citation107] as well as endocytosis of epidermal growth factor receptor (EGFR) [Citation108]. Rab31 overexpression is coupled with unfortunate prognosis in breast cancer patients [Citation109] and is found in estrogen receptor alpha (ERα) positive breast carcinomas [Citation110]. Along with ERα overexpression, MUC1 (mucin 1) which is a heterodimeric transmembrane glycoprotein, is also overexpressed in approximately 90% of breast cancers and forms a complex with ERα that in turn binds to the promoter region of Rab31 and promotes Rab31 expression in an estrogen dependent manner [Citation111,Citation112]. Increased Rab31 levels may up-regulate MUC1 in a positive-feedback loop that influences the prognosis of breast cancers [Citation108].

In addition to endocytic Rabs, exocytic Rabs have also been implicated in cancer progression and malignancy [Citation113,Citation114]. Rab8-containing exocytic vesicles package and deliver matrix metallproteinases (MMP) to the cell surface, and Rab8 is shown to promote MT1-MMP exocytosis, collagen degradation and MDA-MB-231 adenocarcinoma cell invasion [Citation113]. Another exocytic Rab, Rab27B, is also involved in secretion of proinvasive MMPs for degradation of extracellular matrix proteins [Citation114]. In contrast to Rab27A, Rab27B expression level and plasma membrane localization positively correlate with malignant estrogen receptor (ER)-positive breast tumors [Citation114]. Indeed, Rab27B induces G1 to S cell cycle progression and cell proliferation in a lipid modification- and GTP-dependent fashion, and its overexpression increases the invasiveness, tumor size and metastasis of a number of ER-positive breast cancer cell lines both in vitro and in vivo [Citation114].

The same Rab can be up-regulated or down-regulated in different cancers, like the aforementioned Rab31. Rab25 is another well-characterized Rab in this respect and plays a key role in the aggressiveness, prognosis and metastasis of multiple cancer phenotypes including renal cell carcinoma [Citation115], gastric cancer [Citation116], ovarian cancer [Citation117], and lung cancer [Citation118]. Rab25 belongs to the Rab11 subfamily and is also called Rab11c based on sequence homology and is shown to recycle endocytosed membrane proteins [Citation119]. Rab25 can interact with the Rab11 effector Rab coupling protein (RCP) and recycle integrins for plasma membrane remodeling and invasive cell migration [Citation120,Citation121], but its expression is exclusive to the epithelium tissue [Citation122], providing a likely explanation for why Rab25 expression intertwines so closely with epithelium-based cancers. While up-regulated in the aforementioned cancers, interestingly Rab25 is down-regulated in triple-negative breast cancer [Citation123] and colorectal adenocarcinomas [Citation124], which correlates with poor prognosis of patients and displays tumor suppressor property. Whether Rab25 functions as a tumor promoter or a tumor suppressor may be reconciled by the involvement of the chloride intracellular channel protein 3 (CLIC3) in Rab25-mediated integrin recycling and cell invasion [Citation125]. In cell types lacking CLIC3, Rab25 may sort the integrin to lysosomes for degradation and thus inhibit cell invasion behaving like a tumor suppressor, while in cell types with high levels of CLIC3, Rab25 may recycle the integrin to promote cell migration and invasion [Citation125]. In this regard, Rab25 is unique in its GTP-binding motif sequence DTAGLE as opposed to DTAGQE in other Rabs [Citation126], which suggests inhibition of GTP hydrolysis and constitutive activation of Rab25 as a possible mechanism of aggressive metastasis seen in cancers with Rab25 overexpression, similar to the Q61L oncogenic mutation in Ras GTPases.

Alzheimer's Disease

Alzheimer's Disease (AD) is a debilitating form of dementia that affects approximately 5 million new individuals every year and is only treated through symptom management. Increasing evidence has implicated AD as a multifaceted acquired disease caused by multiple factors. In most cases, AD is believed to be initiated by amyloid plaques in the brain tissue that are formed by accumulation of amyloid-beta peptides (Aβ) due to improperly cleaved β-amyloid precursor protein (APP) [Citation127]. The APP gene is located on chromosome 21 and encodes a type 1 integral membrane protein that can be cleaved by proteolytic enzymes (β and γ secretases) upon endocytosis into acidic endosomes to produce Aβ peptides [Citation128–131]. Mutations in these enzymes and the APP gene are shown to have a role in the production of detrimental levels of Aβ associated with AD [Citation127]. In support of the idea of APP processing misregulation in AD pathology, individuals with Down Syndrome (DS) or Trisomy 21 are shown to increase the probability and risk associated with early onset AD, due to an extra copy of the APP gene and elevated levels of APP expression [Citation132,Citation133]. Along this line, in DS mouse models increased expression of APP correlates with decreased retrograde transport of nerve growth factor (NGF) and degeneration of cholinergic neurons [Citation133].

Endosomes are active sites for APP processing in the cell because of the acidic pH favored by the β-secretase, and as a result endosome dysfunction is associated with misregulation of APP processing and AD [Citation134]. In this regard, Rab5 and Rab7 are important regulators of membrane fusion at early and late endosomes, respectively. In AD, the expressions of Rab4, Rab5, Rab7 and Rab27 are up-regulated [Citation135–137] and increased level of Rab5 has been shown to increase APP cleavage and the production of Aβ peptides in fibroblasts, with enlarged endosomes similar to the pathologic endosomal morphology in AD [Citation138]. In DS, a similar enlargement of neuronal endosomes occurs, possibly due to endosomal dysfunction caused by misregulation of APP cleavage and Rab5 activation [Citation132]. In this regard, down-regulation of β−secretase can reduce the production of β-CTF (β−cleaved carboxyl-terminal fragment) as well as the endosomal size [Citation132]. One of the Rab5 effectors APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) that aids in transport of early endosomes containing signaling cargo proteins for gene activation [Citation139–141] can be recruited by β-CTF to endosomes for interaction with and stabilization of Rab5-GTP and up-regulation of Rab5 activity [Citation134], which leads to a positive feedback loop in endosomal dysfunction and Aβ production. Thus, targeting the Rab5 effector protein APPL1 may represent a new therapeutic approach towards stagnation of AD and DS progression.

Conclusion

Rab GTPases are evolutionarily conserved regulators of vesicular transport in all eukaryotic cells. Human cells, in particular, express 66 Rabs some of which are tissue-specific while others show ubiquitous tissue distribution. Both activating and inactivating mutations in Rabs have been identified and implicated in various diseases such as cancer (Rab35 activation), CMT2B (Rab7 activation or inactivation), Warburg Micro syndrome (Rab18 inactivation), Carpenter syndrome (Rab23 inactivation), GS2 (Rab27a inactivation), and XLID (Rab39b inactivation). The investigation of Rab GTPase dysfunction and human diseases has shed light on relative physiological importance of a given Rab and transport pathway in different tissues. For example, the activating Rab7 mutations in CMT2B affect only peripheral neurons, despite its expression in a wide range of tissues and cell types. The mechanism is unclear but it could involve interaction with a tissue-specific effector(s) or represent new Rab function unrelated to its role in membrane transport. This tissue-specific phenotype is also observed in diseases associated with Rab regulators such as CHM, which is caused by mutations in REP-1 that binds Rabs and delivers them to Rab GGTase for prenylation. The Rab GGTase is responsible for post-translational isoprenylation of most Rabs, but the REP-1 mutations in CHM appear to preferentially affect Rab27a and possibly several other Rabs in the retina. In addition to mutations in Rabs and Rab-interacting proteins, increased or decreased Rab expression or activity is associated with devastating diseases like cancer and Alzheimer's. In most cases, however, the cause-effect relationship in the pathogenesis is unclear, which opens new avenues for further research in the field.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Funding

HHS | NIH | National Institute of General Medical Sciences (NIGMS). This work was supported by the NIH under grant R01GM074692 (to GL).

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