Abstract
Local endosomal recycling at synapses is essential to maintain neurotransmission. Rab4GTPase, found on sorting endosomes, is proposed to balance the flow of vesicles among endocytic, recycling, and degradative pathways in the presynaptic compartment. Here, we report that Rab4-associated vesicles move bidirectionally in Drosophila axons but with ananterograde bias, resulting in their moderate enrichment at the synaptic region of the larval ventralganglion. Results from FK506 binding protein (FKBP) and FKBP-Rapamycin binding domain (FRB) conjugation assays in rat embryonic fibroblasts together with genetic analyses in Drosophila indicate that an association with Kinesin-2 (mediated by the tail domain of Kinesin-2α/KIF3A/KLP64D subunit) moves Rab4-associated vesicles toward the synapse. Reduction in the anterograde traffic of Rab4 causes an expansion of the volume of the synapse-bearing region in the ventral ganglion and increases the motility of Drosophila larvae. These results suggest that Rab4-dependent vesicular traffic toward the synapse plays a vital role in maintaining synaptic balance in this neuronal network.
Highlights
The apical compartment of a neuronal cell extends into specific processes forming axons and synapses that are maintained by a distributed endosomal system (Lasiecka et al, 2009)
Synaptic Rab4 Is Maintained through Bidirectional Traffic in Axons with a Moderate Anterograde Bias Rab4, a key endosomal-sorting molecule, is involved in postGolgi membrane sorting throughout the neuron
These observations indicated that Rab4-mRFP could function like endogenous protein, which is marginally enriched at the synapse
Summary
The apical compartment of a neuronal cell extends into specific processes forming axons and synapses that are maintained by a distributed endosomal system (Lasiecka et al, 2009). Recruitment of Rab on sorting intermediate endosomes allows the transfer of vesicular cargoes from early endosomes to recycling endosomes in axons and at synapses (de Renzis et al, 2002; Hoogenraad et al, 2010; Jovic et al, 2010). Endosomal abnormalities found in the cholinergic basal forebrain of patients with Alzheimer’s disease correlate with elevated levels of Rab (Cataldo et al, 2000). All these reports suggest that Rab4-dependent vesicle sorting is essential for the development and maintenance of the nervous system
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