Parkinson’s disease (PD) is the second most prevalent chronic neurodegenerative disorder of aging, clinically characterized by motor symptoms including resting tremor, muscle rigidity, bradykinesia, postural instability and various non-motor symptoms (Shi et al., 2016). The most evident pathological features are the progressive degeneration of dopaminergic neurons and axonal projections in the substantia nigra and the wide spreading of eosinophilic Lewy bodies whose cardinal component is α-synuclein detected in some surviving neurons (Goedert et al., 2013).

The etiology underlying the development of PD remains elusive. To date, approximate 18 genes have been identified as the genetic causes for familiar PD, which have provided critical clues for the pathogenesis of the disease (Atashrazm and Dzamko, 2016). Recently, accumulating genetic discoveries have revealed the association between vesicle trafficking and PD (Zimprich et al., 2011; Edvardson et al., 2012; Wilson et al., 2014). Disruption of the cellular vesicle trafficking results in the impaired degradation of certain proteins and further leads to the abnormal protein aggregation, which exerts a toxic effect on neurons (Mazzulli et al., 2016). Rab GTPases (Rabs) perform the basic functions in intracellular trafficking events (Figure 1). Moreover, a series of recent studies have revealed that certain Rabs are involved in the modulation of α-synuclein. Impairment of these proteins have been reported to be one of the rare causes for inherited early onset PD (Wilson et al., 2014; Lesage et al., 2015; Mata et al., 2015; Shi et al., 2016). These new findings provide a novel insight into the molecular pathogenesis of PD. Moreover, the pathogenic mechanisms of different PD-related genes (SNCA, LRRK2, PINK1, Parkin and TMEM230) may share a converging molecular pathway, and Rabs may serve as potential modulators in this pathway. In this review, we summarize the physiological functions of Rabs and their interactions with multiple PD-related genes (Table 1).

Rabs are the largest subfamily of Ras-like GTPases with more than 60 members in the human genome and 11 members in the yeast, serving as molecular “switches” in vesicle trafficking (Pereira-Leal and Seabra, 2001). Generally consisting of 200 amino acids, Rabs are widely distributed across the eukaryotic cells. They perform the essential functions in the formation, maturation, transport, tethering and fusion of vesicles, regulating the interactions among the major organelles and maintaining the cellular homeostasis (Binotti et al., 2016). Some structural features of the primary structure contribute to the specific interactions among membranes (Pereira-Leal and Seabra, 2000; Lipatova et al., 2015). The GTP-binding regions are highly conserved in evolution and make Rabs present in inactive GDP-bound and active GTP-bound forms. The CAAX boxes usually contain two cysteine residues and facilitate the attachment of Rabs to the membrane after prenylation. Located upstream at CAAX boxes, the hypervariable region may enable targeting Rabs to the specific effectors. Additionally, the Rab family (RabF) motifs (RabFl∼RabF5) serve to differentiate Rabs from other members of the Ras superfamily; the Rab subfamily (RabSF) sequences play an important part in the identification of various subfamilies (Pereira-Leal and Seabra, 2000). Some studies indicate that apart from the diversity of C-terminal, RabF and RabSF are also important for the specific interactions with target effectors and membranes (Ali and Seabra, 2005). The GTPase fold contains a six-stranded sheet and five α helices which are interconnected by 10 loops. Different forms of nucleotide-bound Rabs present distinct conformation involving the switch I and switch II regions (Stroupe and Brunger, 2000). Through the cycle between active and inactive states, Rabs achieve the function as molecular “switches.” The new inactive GDP-bound form interacts with Rab escort protein (REP) and is delivered to a geranylgeranyl transferase (GGTase) (Alexandrov et al., 1994). After prenylation, the Rab GDP dissociation inhibitor (GDI) recognizes the GDP-bound Rab and regulates the specific insertion to the membrane with the assistance of a GDI dissociation factor (GDF) (Sivars et al., 2003). Once the Rab interacts with the target membrane, it transforms from the GDP-bound form to the GTP-bound form, a reaction that is catalyzed by guanine nucleotide exchange factor (GEF) (Delprato et al., 2004). The active GTP-bound form is recognized by the effector proteins including sorting adaptors, tethering complexes, motor proteins and various enzymes (Hutagalung and Novick, 2011). Followed by hydrolysis which is stimulated by the GTPase activating protein (GAP), the trafficking event comes to an end (Pan et al., 2006).

Vesicle trafficking in the clathrin-dependent or clathrin-independent manner is the core process for the cellular membrane dynamics. Numerous Rabs are involved in the budding, uncoating, motility and fusion of vesicles via interaction with the relevant effectors. Once a Rab stimulates the association between the sorting adaptor and the distinct receptor, the cargo is shipped into a budding vesicle. Rab9, whose effector is TIP47, facilitates the interaction between TIP47 and cytoplasmic terminal of mannose-6-phosphate receptors (M6PRs) during the formation of vesicles and maintains the recycle of M6PRs from the late endosome to the trans-Golgi network (TGN) (Aivazian et al., 2006). Coated vesicles account for most of the membrane trafficking, and the coats are removed to allow the fusion of vesicles. The assembly polypeptide 2 (AP2) is crucial for the recruitment of clathrin, of which the μ2 subunit interacts with the cargo after phosphorylation by μ2 kinase (Jackson et al., 2003). Rab5 is involved in the regulation of vesicle uncoating via either the removal of μ2 kinase or the turnover of phosphatidylinositol-4, 5-biphosphate [PI (4, 5) P2] (Semerdjieva et al., 2008). To validate the correct delivery of vesicles to the relevant membranes, it is necessary for Rabs to mediate vesicle trafficking along a series of motor proteins and microtubules. For example, myosin Va is linked to Rab27 by melanophilin working as an adaptor protein, and then delivers the relevant vesicles to the pericellular matrix to allow melanocytes to achieve their physiological functions (Wu et al., 2002). To ensure the specificity of membrane fusion, Rabs may cooperate with tethering factors and mediate interactions between vesicles and the relevant membrane. As a result of the overlapping binding site of endosome antigen 1 (EEA1) for Rab5 and syntaxin-6, Rabs may interact directly with SNAREs and regulate the docking and fusion with target membranes (Simonsen et al., 1999).

α-Synuclein is a small protein encoded by SNCA, whose role in the pathogenesis of PD has been highly debated over the years. Initially identified as a presynaptic protein, α-synuclein may play an important role in endo- or exocytosis of synaptic vesicles (Hansen et al., 2011). Recent studies revealed that α-synuclein diffused among the cells via a prion-like transmission, and the presence of extracellular α-synuclein challenged the previous notion indicating that α-synuclein was limited to the cytoplasm (El-Agnaf et al., 2003; Lee et al., 2006; Desplats et al., 2009; Hansen et al., 2011). As for lacking a signal sequence, part of extracellular α-synuclein has been confirmed to translocate across the membrane via the exocytosis pathway, which relies on calcium rather than the conventional manner, and the process is promoted under the stressing conditions (Lee et al., 2005; Jang et al., 2010; Emmanouilidou and Vekrellis, 2016). Additionally, extracellular α-synuclein can also return to the neurons via endocytosis or the clathrin-dependent manner (Liu et al., 2007; Lee et al., 2008). All of the above studies have shed new light on the role of α-synuclein in the pathogenesis of PD and indicate the possible interactions between α-synuclein and Rabs which play a critical role in modulating the vesicle trafficking.

A large number of studies have made efforts to clarify the interactions between Rabs and α-synuclein, and this field can be elucidated from two different perspectives. On the one hand, by a train of immunofluorescence, co-immunoprecipitation and other strategies, certain Rabs (Rab3a, Rab5, Rab8, Rab7, and Rab11a) have been confirmed to interact with α-synuclein in different models and protect cells from the toxicity induced by the mutation or over-expression of α-synuclein (Hasegawa et al., 2011; Chutna et al., 2014). α-Synuclein accumulation is liable to collapse endoplasmic reticulum-Golgi trafficking during the process of tethering or docking in a manner of dose and time dependence, which can be alleviated by overexpression of Ypt1/ Rab1 which helps the COPII vesicles uncoating in yeast or dopaminergic neurons (Cooper et al., 2006; Gitler et al., 2008). The interaction between Rab1 and α-synuclein may be mediated by prenylated Rab acceptor protein (PRA1) which serves as a GDF for Rab1 (Lee et al., 2011). Using a Drosophila model, Breda et al. (2015) revealed that overexpression of Rab11 colocalizing with α-synuclein in intracellular inclusions could significantly reverse the synaptic potentiation at the neuromuscular junction due to the increase of synaptic vesicle size. Through a shRNA-based screen, some Rabs (Rab8b, Rab11a, and Rab13) have been identified as modulators of α-Synuclein in living cells and reduced the toxicity induced by aggregated α-synuclein via secretion enhancement (Goncalves et al., 2016). Rab8, playing a role in the post-Golgi trafficking, binded with the C terminal of α-synuclein, which was confirmed by the nuclear magnetic resonance spectroscopy. In cell models, Rab8 suppressed the toxicity caused by mutation or overexpression of α-synuclein (Yin et al., 2014). On the other hand, Rabs may be involved in regulating the recycling and distribution of α-synuclein, which opens a new window for new therapeutic strategies. Apart from degradation by the lysosomal pathway, the internalized extracellular α-synuclein might be partly secreted from cells via exocytosis, which might be facilitated by Rab11 (Liu et al., 2009; Chutna et al., 2014). Chutna et al. (2014) conducted a further study that showed the co-localization of Rab11 and α-synuclein in vivo. In addition, they also found that Rab11 rescued the α-synuclein aggregation and cytotoxicity. However, the mechanism underlying how Rab11 regulates the secretion of α-synuclein is still disputed (Chutna et al., 2014). Besides, the downregulation of the novel disease-causing gene Rab39b results in the dysregulation of α-synuclein homeostasis, which will be extensively elucidated below (Wilson et al., 2014). As a protein regulating synaptic vesicles, Rab3a not only has been confirmed to have a close association with α-synuclein but also may lead to the re-distribution of α-synuclein via a conformation change (Chen et al., 2013). Recently, Rab35 was identified as a potential biomarker in the serum for the differential diagnosis and progression of PD. Besides, the functional study also suggested that overexpression of Rab35 led to increased aggregation and secretion of aberrant α-synuclein (Chiu et al., 2016). Above all, these lines of evidence suggest that the α-synuclein pathology propagation may partly attribute to the dysregulation of Rabs.

Over the years, many researchers have paid much attention to exploring the pathogenesis of PD to halt or slow the progression of PD and identify effective therapeutic strategies. Different hypothesizes have been proposed, such as mitochondrial dysfunction, protein misfolding and aggregation, and impaired autophagy-lysosome system. Recently, the focus has shifted to vesicle trafficking. In this review, we emphasized the importance of the functions of Rabs and their potential interplay with different PD-related genes. Rabs perform an essential role in vesicle trafficking and cellular homeostasis maintenance. Not only are Rabs closely associated with α-synuclein-mediated pathological process but they also interact with many genes whose mutations or polymorphisms lead to the development of PD. It is plausible that Rabs could be regarded as novel biomarkers or therapeutic targets before the clinical manifestation of PD. However, the role of Rabs in the molecular pathway of PD remains elusive. More functional studies should be conducted to reveal the interplay between Rabs and different effectors.

This study did not involve any ethical issues. The studies about MC1R and Rab39b received approval from the institutional ethics committee of Zhengzhou University.

The conception or design of the work: M-mS, C-hS, and Y-mX. Drafting the work or revising it: M-mS, C-hS and Y-mX. Final approval of the version to be published: M-mS, C-hS, and Y-mX. Agreement to be accountable for all aspects of the work: M-mS, C-hS, and Y-mX.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.