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Principal Investigator: Avital Adah Rodal
Organization: BRANDEIS UNIVERSITY
Fiscal Year: 2024
Award: $463,903
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
The goal of this proposal is to understand how cellular membrane trafficking machinery controls the packaging
and release of extracellular vesicle (EV) cargoes from synapses in vivo. EVs are small membrane-bound
vesicles released by numerous cell types, including neurons, carrying cargoes critical for signaling and
disease. However, we understand very little about how EV cargo traffic is spatially and temporally regulated
within the polarized and complex morphology of neurons. We have developed tools to track and manipulate EV
traffic at Drosophila presynaptic terminals in vivo, and discovered that flux of cargoes through a plasma
membrane-recycling endosome route determines whether they are locally sorted for packaging and release in
EVs, rather than depleted from synapses by retrograde transport. Recycling endosomes have primarily been
studied in non-neuronal cells, and very little is known about their lifetime, functions, or dynamics at presynaptic
terminals. We do know that recycling endosomes play critical roles in signaling, neuronal morphogenesis, EV
traffic, and synaptic transmission. Understanding and therapeutically intervening in these important processes
will require a deeper knowledge of the mechanisms of neuronal recycling endosome function. In this proposal,
we will elucidate the mechanisms of synaptic EV cargo and recycling endosome traffic in vivo. To achieve
these goals, we will use Drosophila genetics, biochemistry, high-resolution microscopy, and live cell imaging.
1) We will determine the functions, dynamics, and regulation of different types of synaptic recycling
endosomes. To this end, we will develop new tools and approaches to define and control functionally distinct
recycling compartments at synapses. Using these tools, we will test novel mechanistic hypotheses for how
membrane traffic machinery sorts cargoes at synaptic recycling compartments. 2) We will determine how EV
cargo traffic depends on distinct modes of synaptic endocytosis: clathrin-mediated endocytosis, which operates
under low neuronal activity and activity-dependent bulk endocytosis, which operates during intense neuronal
activity. These experiments will ascertain if EV fate is determined by different modes of internalization, how
recycling endosomes contribute to these functions, and provide new mechanisms to link activity, endosomal
traffic, and EV release. Given the conserved nature of synaptic membrane trafficking machinery, our findings
and tools will lay the foundation for new insights into EV traffic in many aspects of nervous system function,
including in human neurological disease.
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