Exploring the dendritic molecular machinery responsible for neuronal polarization

Description du projet

Aperçu mécanistique de la polarisation neuronale

Les neurones sont des cellules fortement polarisées qui se composent d’un seul axone et de plusieurs dendrites, assurant la circulation directionnelle des informations dans le système nerveux. Les dendrites reçoivent des signaux entrants tandis que les axones transmettent ces signaux aux cellules cibles. Pour répondre à la question cruciale en neurobiologie concernant la manière dont les neurones acquièrent cette polarité, le projet SortAx financé par l’UE se concentre sur le rôle des endosomes. Les chercheurs étudient le mécanisme par lequel les endosomes trient et transportent les protéines vers l’axone. Les résultats apporteront non seulement des connaissances fondamentales sur la biologie des neurones, mais aideront également à comprendre comment ces processus engendrent des maladies neurodégénératives telles que la maladie d’Alzheimer.

Objectif

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 aging.

During the past 30 years, researchers have been able to dissect the mechanisms required to target proteins to the dendritic plasma membrane, however our understanding of the mechanisms underlying the axonal polarization of proteins is rather incomplete. In this regard, a growing number of studies, including my work, suggests that dendritic endosomes are key sorting stations to direct neuronal cargoes to the axon. Yet, the molecular machinery of intracellular trafficking and endosomal sorting required remains to be uncovered.

In this proposal, I hypothesize that dendritic endosomes are key sorting stations for polarization of axonal cargoes. I therefore propose to elucidate the key axonal trafficking pathways of endogenous cargoes, the intracellular trafficking and endosomal machinery involved and assess their importance for axonal development and connectivity. Importantly, I 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 has been followed for a limited number of cargoes under overexpression conditions.

Given that abnormal axonal trafficking increases susceptibility to neurodegenerative diseases, including Alzheimer´s and Parkinson, with this project I will also contribute to the design of new therapies to alleviate neurodegeneration by deciphering the molecular mechanisms of axonal cargo trafficking.