# The role of a novel viral-like signalling pathway in synaptic plasticity and neurological disorders

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $366,406

## Abstract

We have discovered a novel viral-like signaling pathway associated with extracellular vesicles (EV). We
found the Drosophila homolog of ARC (Actin-Regulated Cytoskeleton-associated protein) (darc1), is
present in EVs as both an mRNA and protein. ARC is a master regulator of synaptic plasticity in the nervous
system of mammals and is crucial for learning and memory. dArc1 bears a domain resembling
retroviral/retrotransposon Gag-like proteins that multimerizes into a capsid that packages viral RNA. Our
work shows dARC1 forms a capsid, associates with its own RNA, and then transports the darc1 transcript
across the synapse. The transfer of dArc1 is needed for activity-dependent plasticity at the fly
neuromuscular junction (NMJ). Besides dArc1, it is unknown whether other genes are in this viral-like
pathway. We address this uncertainty in Aim 1. Here we describe our plan to identify other Gag-like
proteins in EVs, and we have already found another Gag protein enriched in EVs, that is encoded by the
retrotransposon Copia. We have found that Copia transfers across the synaptic bouton. When copia is
knocked down at the NMJ this strikingly leads to increased plasticity. This is the opposite of darc1, where
we reported a decrease in plasticity. In Aim 2 we focus on what cargoes are co-transferring with dArc1 and
Copia. We have identified through co-immunoprecipitation, mRNAs and proteins that associate with dArc1
and Copia. As to how the transfer of Arc occurs, we have found that the dArc1 3’untranslated region (UTR)
is necessary and sufficient for the transfer of dArc1 across synaptic boutons. We are now testing if the
dArc1 3’UTR directs the loading of dArc1 into EVs. As well, we propose experiments to understand how
darc1 and copia mediate synaptic plasticity. We have co-immunoprecipitated dArc1 and Copia to identify
potential interactors, and we will take a candidate approach to find genetic interactors. In preliminary work
we found that dArc1 is needed for proper WNT pathway signaling at the NMJ. Additionally, we observe
that Copia and dArc1 bind to some of the same proteins and mRNAs, suggesting that they may be
antagonistic to each other, thus potentially explaining their seemingly opposite roles in mediating plasticity.
Through this grant we will expand our understanding of EV trafficking and synaptic plasticity, while
describing a novel physiological function of a retrotransposon in neuronal communication.

## Key facts

- **NIH application ID:** 10430205
- **Project number:** 5R01NS112492-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Travis Thomson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $366,406
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430205

## Citation

> US National Institutes of Health, RePORTER application 10430205, The role of a novel viral-like signalling pathway in synaptic plasticity and neurological disorders (5R01NS112492-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10430205. Licensed CC0.

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