Genetic Analysis in Drosophila Reveals a Novel Role for the ESCRT Component VPS24 in Synaptic Transmission

Open Access
Cao, Kerry
Area of Honors:
Bachelor of Science
Document Type:
Thesis Supervisors:
  • Fumiko Kawasaki, Thesis Supervisor
  • Bernhard Luscher, Honors Advisor
  • Drosophila
  • VPS24
  • synaptic
  • transmission
  • paralysis
  • genetics
  • vesicle
  • neurotransmitter
Understanding the in vivo molecular mechanisms of synaptic transmission remains a major objective in cellular and molecular neuroscience. Our genetic analysis of synaptic transmission has identified a novel synaptic mechanism involving the Endosomal Sorting Complexes Required for Transport (ESCRT) pathway previously implicated in intracellular membrane trafficking. A forward genetic screen for new mutations affecting synaptic transmission involved chemical mutagenesis with ethyl methanesulfonate (EMS) followed by screening for third chromosome mutations affecting fly behavior. A new mutation was recovered in the vps24 gene, which encodes a conserved protein component of the ESCRT-III complex which functions in targeting proteins to multivesicular bodies (MVBs) for degradation. The new Drosophila vps24 mutant exhibits defects in neurotransmitter release and provides the first evidence implicating the ESCRT pathway in synaptic transmission. Surprisingly, VPS24 was found to be localized in proximity to neurotransmitter release sites at active zones (AZs), suggesting a novel ESCRT-mediated mechanism contributing to neurotransmitter release. Furthermore, our preliminary studies of other ESCRT proteins indicate function and localization of this pathway within the presynaptic terminal. Ongoing studies have involved generation of Drosophila transgenic lines and further in vivo analysis of the VPS24 protein properties and functions in synaptic transmission. Given the strong evolutionary conservation of the ESCRT pathway, it is anticipated that these studies will be of general significance to our understanding of the ESCRT pathway and its importance in neural function.