Uncovering the molecular machinery responsible for cargo sorting in neuronal polarization

Overview

Project Summary

The high morphological and functional polarization of neuronal processes relies on exquisite mechanisms to accurately sort and traffic proteins to their rightful location. It is therefore of no surprise that accurate formation and function of neuronal circuits depends on these trafficking mechanisms, which are indeed often impaired in neurodegenerative disorders and normal ageing. During the past 30 years, researchers have been able to decipher the mechanims required to target proteins to the dendritic plasma membrane; however, our understanding of the mechanisms underlying axonal polarization of proteins is rather incomplete. In this regard, a growing number of studies, including my work, suggest that dendritic endosomes are key sorting stations to direct neuronal cargoes to the axonal membrane. Yet, the protein machinery of intracellular trafficking and endosomal sorting required remain to be uncovered. In particular, I have recently described that SorCS1-Rab11FIP5 protein complex localizes to dendritic endosomes to sort internalized Neurexin (Nrxn), a canonical axonal cargo, from early to recycling endosomes, thus promoting the trafficking of Nrxn-containing recycling endosomes to the axon. Notably, other canonical axonal cargoes have also been shown to tranverse endosomes in the somatodendritic compartment during their trafficking route to the axon. These observations suggest that there are likely many regulators of intracellular trafficking and endosomal sorting in dendrites, such as sorting receptors and adaptor proteins, which localize to endosomes and interact with different neuronal cargoes to direct them to the axon. Therefore, in this proposal we hypothesize that dendritic endosomes are key sorting stations for polarization of axonal cargoes. In order to test this hypothesis, we propose to elucidate the key axonal trafficking pathways of endogenous cargoes, dissect the dendritic molecular machinery of intracellular trafficking and endosomal sorting involved and assess their importance for axonal development in vitro and brain connectivity in vivo. Importantly, we will adopt an unbiased approach using cutting-edge technology to focus on the endogenous protein pool, which differs considerably from prior studies in the field, in which axonal trafficking route was followed only for a limited number of cargoes under ectopic expression. Given that abnormal axonal trafficking increases susceptibility to neurodegenerative diseases, including Alzheimer´s and Parkinson, this research plan is in alignment with the UN2030 agenda once it will contribute to the design of new therapies to alleviate neurodegeneration by deciphering the molecular mechanisms of axonal cargo trafficking.

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