The Role of a Neuron-Specific V-Atpase in Synapse Specification, Function, and Maintenance

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Title: The Role of a Neuron-Specific V-Atpase in Synapse Specification, Function, and Maintenance
Author: Williamson, Wallace Ryan
Abstract: The Vacuolar -type (V - ) adenosine triphosphatase (ATPase ) is a proton -pumping nanomachine consisting of two multi -subunit , reversibly associating protein sectors , the cytosolic V1 sector and the membrane -bound Vo sector . The V1 /Vo holoenzyme hydrolyses ATP to translocate protons across biological membranes thereby modulating lumenal and extracellular pH . Additionally , accumulating evidence suggests that the Vo sector has a role in membrane fusion when dissociated from the V1 sector , its proton -pumping partner . Published evidence for this includes a null allele for the neuron -specific a subunit in the Drosophila Vo sector , v100 , which leads to defects in synaptic function that are unrelated to pH regulation . My project emerged from the need to explain why v100 has two additional phenotypes that are absent in other synaptic function mutants : functional and structural degeneration in photoreceptor cells and patterning defects in the visual system neuropil . I proposed that v100 has a previously undocumented role on a neuron -specific endo /lysosomal pathway in addition to its documented role in neurotransmitter secretion . To test my hypothesis in the context of only one of the two purported v100 functions , I generated transgenic animals with v100 mutations designed to specifically disrupt either acidification or membrane fusion . Using these genetic tools , I discovered that v100 has an essential role in sorting cargo into an endo -lysosomal pathway that concomitantly requires v100 for the acidification -dependent maturation of degradation -competent organelles . This 'sort -and -degrade' mechanism for v100 defines a neuron -specific degradation pathway that is required for synaptic specification , function , and maintenance . In developmental stages , v100 is required to 'sort -and -degrade' guidance receptors as part of the synapse specification program . In the adult , the 'sort -and -degrade' mechanism provides additional degradative capacity to neurons , a cell type that must often maintain homeostasis for unusually long periods of time . Finally , I provide evidence that the role for V100 in membrane fusion requires a direct , physical interaction with Syntaxin -1 , an interaction that can be specifically disrupted in vitro and in vivo . In brief , my results provide mechanistic insight into the acidification -independent role of v100 and reveal the existence of a neuron -specific endo -lysosomal pathway on which v100 functions to 'sort -and -degrade' cargo in order to meet the special needs of a neuron in development , function , and maintenance . [Keywords : Drosophila , intracellular trafficking , development , degeneration , lysosomal , endosomal , degradation , acidification]
URI: http : / /hdl .handle .net /2152 .5 /1102
Date: 2012-08-13

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The Role of a Neuron-Specific V-Atpase in Synapse Specification, Function, and Maintenance. Granduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /1102 .

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