Vps54 Regulates Lifespan and Locomotor Behavior in Adult Drosophila melanogaster

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.

Defects in Glutathione System in an Animal Model of Amyotrophic Lateral Sclerosis

“…The wobbler mouse displays a point mutation affecting VPS54, a component of the Golgi-associated retrograde protein (GARP) complex, tethering endosome-derived vesicles to the trans-Golgi network [12]. Recently, Wilkinson discovered that the specific disruption of both scattered (scat), the fly VPS54 ortholog, and Rab11 gene expression result in muscle atrophy and reduced climbing ability in Drosophila [79]. Thus, there might be a connection between the VPS54 mutation and disturbed EAAT3 recycling at the plasma membrane, aggravating an impaired cysteine supply and glutathione synthesis in neurons.…”

Golgi-associated retrograde protein (GARP) complex recruits retromer to trans-Golgi network for FgKex2 and FgSnc1 recycling, necessary for development and pathogenicity ofFusarium graminearum

“…These consequences encompass heightened protein secretion, disrupted autophagy patterns, and anomalies in vacuolar morphology 15 . Beyond yeast, the removal of GARP has been linked to infertility in worms 61 , reduced lifespans in flies 62 , and embryonic lethality in mice 63 . Nevertheless, the role of the GARP complex in pathogenic fungi remains inadequately explored through systematic studies.…”

Role of GARP Vesicle Tethering Complex in Golgi Physiology

“…Although all GARP subunits are dispensable for life in yeasts [ 1 ], deletion of GARP causes an increased protein secretion, abnormal autophagy, and defects in vacuolar morphology [ 4 , 5 ]. GARP deletion also causes infertility in worms [ 54 ], a shorter life span in flies [ 53 ], and embryonic lethality in mice [ 55 ]. In this section, we have summarized the major described roles of GARP proteins in cell physiology.…”