Critical importance of RAB proteins for synaptic function

Abstract

Neurons are highly polarized cells that exhibit one of the more complex morphology and function. Neuronal intracellular trafficking plays a key role in dictating the directionality and specificity of vesicle formation, transport and fusion, allowing the transmission of information in sophisticate cellular network. Thus, the integrity of protein trafficking and spatial organization is especially important in neuronal cells. RAB proteins, small monomeric GTPases belonging to the RAS superfamily, spatially and temporally orchestrate specific vesicular trafficking steps. In this review we summarise the known roles of RAB GTPases involved in the maintenance of neuronal vesicular trafficking in the central nervous system. In particular, we discriminate the axonal pre-synaptic trafficking and dendritic post-synaptic trafficking, to better underlie how a correct orchestration of vesicle movement is necessary to maintain neuronal polarity and then, to permit an accurate architecture and functionality of synaptic activity.

Keywords: RAB GTPases; axon; dendrite; neuronal cells; neuronal trafficking; post-synaptic; pre-synaptic; synaptic function; vesicle transport.

Figure 1.

RAB GTPases orchestrate different neuronal trafficking steps. Graphical representation of RAB GTPase-mediating intracellular vesicular trafficking steps in different neuronal cell compartments. Section A (in red) represents the cell body compartment with RAB GTPases that mediate ER-Golgi pathway and vice versa. RAB1, RAB2, RAB8, RAB39B are involved in anterograde traffic and RAB7, RAB6, RAB33B, RAB2 play a role in retrograde transport. Section B (in blue) shows RAB proteins involved in dendritic vesicle trafficking. RAB8, RAB10, RAB11 controls constitutive Membrane Precursors Vesicle (MPV) trafficking in secretory pathway from cell body to the cell periphery. RAB17 acts at early neuronal developmental stage in secretory pathway through MPV for dendritic morphogenesis. RAB21 controls the exocytic vesicle transport to the cell periphery. A specialized function is showed for RAB11 in TrkB receptor (white rectangle) internalisation leading to local receptor signal increase for dendritic arborisation. Section C (in yellow) recapitulates RAB GTPases involved in axonal vesicle trafficking. Transport vesicles (TV) and recycling endosomes (RE) are involved in axonal outgrowth. RAB10, RAB33A and RAB27B mediate TV trafficking. RAB10 controls the vesicle transport from TGN to the plasma membrane. RAB27B regulates the anterograde transport of neurotrophin receptors and RAB33A mediates anterograde synaptophysin-positive vesicles. RAB4, RAB11, RAB35 and RAB13 are involved in RE pathway. RAB4 and RAB11 control RE fast and slow recycling route, respectively. RAB25 and RAB14 collaborate with RAB11. RAB35 permits neurite and axon elongation together with RAB8, RAB13 and RAB26. RABs reported in italic, represent the finding of their presence on RE without a well-defined role in neuron. RAB5 and RAB7 have been shown to sequentially mediate the retrograde transport of NGF and neurotrophin receptors from RAB5-positive Early Endosomes (EE) to RAB7-positive Late Endosomes (LE), leading to axonal degeneration. Section D recapitulates RAB proteins involved in pre- (green) and post- (orange) synaptic functions. At pre-synaptic site, RAB3 and RAB27B play a role in specific steps of SV docking and exocytosis at the pre-synapse. Recycling of SVs by endocytosis is directed through several pathways, represented are kiss-and-run and clathrin-mediated endocytosis (CME). The first step of CME is mediated by RAB5, RAB10 and RAB14. Then, RAB10 and RAB14 control the SVs direct pathway and RAB5 directs the endosomal pathway via RE. RAB5-mediated RE trafficking involves at the end, RAB4, RAB11 and RAB35 in SV regeneration. RAB7, driving LE-positive vesicles from RAB5-positive EE, links endosomal-recycling pathway to the autophagic process. RAB26, RAB33B and RAB35 are involved in SV degradation via the autophagic pathway. At the post-synaptic site, RAB17 controls kinate receptor (white triangle) surface expression. RAB39B and RAB8 are involved respectively, in GluA2/GluA3- and GluA1-AMPA receptor (white ellipse) trafficking and delivery. RAB11 is the mediator of recycling endosomes and contributes with RAB8 to AMPAR delivery. RAB5, controlling EE, is involved in a clathrin-dependent receptor internalization. Through RAB4 and RAB11receptors are recycled to the plasma membrane, and through RAB7-dependent late endosomes they are transported toward lysosomes.