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Abstract
Vps54 is an integral subunit of the Golgi-associated retrograde protein (GARP) complex, which is involved in tethering endosome-derived vesicles to the trans-Golgi network (TGN). A destabilizing missense mutation in Vps54 causes the age-progressive motor neuron (MN) degeneration, muscle weakness, and muscle atrophy observed in the wobbler mouse, an established animal model for human MN disease. It is currently unclear how the disruption of Vps54, and thereby the GARP complex, leads to MN and muscle phenotypes. To develop a new tool to address this question, we have created an analogous model in Drosophila by generating novel loss-of-function alleles of the fly Vps54 ortholog (scattered/scat). We find that null scat mutant adults are viable but have a significantly shortened lifespan. Like phenotypes observed in the wobbler mouse, we show that scat mutant adults are male sterile and have significantly reduced body size and muscle area. Moreover, we demonstrate that scat mutant adults have significant age-progressive defects in locomotor function. Interestingly, we see sexually dimorphic effects, with scat mutant adult females exhibiting significantly stronger phenotypes. Finally, we show that scat interacts genetically with rab11 in MNs to control age-progressive muscle atrophy in adults. Together, these data suggest that scat mutant flies share mutant phenotypes with the wobbler mouse and may serve as a new genetic model system to study the cellular and molecular mechanisms underlying MN disease.
Highlights
Neurodegenerative diseases are severe and often fatal disorders associated with reduced function, or loss of function, of neurological components
Like phenotypes observed in the wobbler mouse, we show that scat mutant adults are male sterile and have significantly reduced body size and muscle area
One of the primary objectives of this study was to determine whether disruption of scat expression in adult flies caused phenotypes like those observed in the wobbler mouse
Summary
Neurodegenerative diseases are severe and often fatal disorders associated with reduced function, or loss of function, of neurological components. This degeneration commonly leads to cognitive impairment and/or motor dysfunction. The identification of mutations linked to human neurodegenerative diseases have highlighted several important intracellular pathways that are involved in disease pathogenesis. Many of these genes can be categorized by their contribution to critical intracellular processes including RNA and protein metabolism, axonal and cytoskeletal dynamics, and membrane trafficking (Taylor et al, 2016). Disruption of pathways involved in the function of endocytic trafficking has been linked to
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