Abstract
Early endosomal membrane compartments are required for the formation and recycling of synaptic vesicles, but how these compartments are regulated is incompletely understood. We performed a forward genetic screen in C. elegans for mutations that affect RAB-5 labeled early endosomal compartments in GABAergic motoneurons. Here we report the isolation and characterization of one mutation, rabx-5. The rabx-5 mutation leads to decreased intensity of YFP::RAB-5 in the cell soma but increased intensity in the synaptic and intersynaptic regions of the axon. This effect is due to the bias of the cycling state of RAB-5, and results from a change in the organization of the early endosomal compartment as well as the membrane binding state of RAB-5. Synaptic vesicle accumulation is altered in rabx-5 mutants, and synaptic transmission from cholinergic neurons is decreased. Early endosomal membrane compartments show disorganization with ageing and rabx-5 mutant animals age faster. These results suggest that rabx-5 regulation of RAB-5 compartments is important for maintaining proper synaptic function throughout the lifetime.
Highlights
Synaptic vesicle formation and neurotransmission require precise regulation of the proteins and lipids of the exocytic and endocytic pathways [1,2,3]
We demonstrate that RABX-5 is the guanine exchange factor for RAB-5 in neurons and describe the effects of rabx-5 and rab-5 disruption on endosomal populations, synaptic vesicles, locomotion, and ageing
We demonstrate that Rabx-5 is an important regulator of RAB-5 endosomal compartments and synaptic vesicles in neurons of C. elegans
Summary
Synaptic vesicle formation and neurotransmission require precise regulation of the proteins and lipids of the exocytic and endocytic pathways [1,2,3]. Synaptic vesicles contain numerous members of the Rab family of membrane regulators [4,5,6] suggesting interactions with multiple endosomal populations during formation, secretion, and recycling. In the activated GTP-bound state, Rab GTPases associate with specific membrane compartments through their C-terminal prenylation motifs. There, they regulate membrane trafficking by recruiting effector proteins that bind to proteins responsible for budding and fusion [7]. Specific Rab proteins act as ‘‘intracellular cargo address labels’’ [7,8]. Rab-5 functions mainly in early endosomes, Rab-7 is present in late endosomes, and Rab-11 associates with recycling endosomes [9,10]
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