The goal of this project is to understand mechanisms of trans-synaptic communication during development and plasticity of synapses. During the past many years, with support from this grant, we have pioneered work with fundamental implications to our understanding of synaptic plasticity signals, demonstrating an essential role for Wnts in these processes. The linkage between Wnts and severe neurological conditions, such as Alzheimer?s disease, and schizophrenia1,2, makes our findings particularly impactful. During the past 5 years, the funding stability provided by this MERIT award, enabled us to significantly expand our field of expertise, which resulted in several highly significant and unexpected discoveries, which form the basis of the work proposed over the next 5 years of the award. In particular, we documented a totally novel mode of intercellular communication, ViSyToR (Viral Synaptic Transfer of RNA) a retroviral-like mechanism of trans-cellular mRNA transfer. In addition, we provided compelling evidence that ViSyToR was used to carry mRNA encoding a master regulator of synaptic plasticity, Arc/Arg2.1. In the proposed extension of this MERIT award we will (a) test the hypothesis that Copia retrotransposon forms have a physiological role in trans-synaptic communication, (b) determine if other Gag-encoding genes and transposons function in trans-synaptic communication using the ViSyToR pathway, and (c) unravel mechanisms of ViSyToR function at synapses, including interactions between Wg and dArc1.
Understanding mechanisms of communication between cells in the nervous system is crucial to elucidating the processes that go awry in neurological disorders, such as Alzheimer?s disease and schizophrenia. This projects centers on the discovery and characterization of a novel mechanism of cellular communication in the nervous system, called ViSyToR (Viral Synaptic Transfer of RNA) using viral-like processes to transmit a signal across cells. The results from these studies are expected to significantly expand our knowledge of signal transmission in the nervous system and provide platforms for the development of therapies to treat neurological diseases.
|Ashley, James; Cordy, Benjamin; Lucia, Diandra et al. (2018) Retrovirus-like Gag Protein Arc1 Binds RNA and Traffics across Synaptic Boutons. Cell 172:262-274.e11|
|Budnik, Vivian; Ruiz-Cañada, Catalina; Wendler, Franz (2016) Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci 17:160-72|
|Packard, Mary; Jokhi, Vahbiz; Ding, Baojin et al. (2015) Nucleus to Synapse Nesprin1 Railroad Tracks Direct Synapse Maturation through RNA Localization. Neuron 86:1015-1028|