Exploring the dendritic molecular machinery responsible for neuronal polarization

Descripción del proyecto

Información mecanicista de la polarización neuronal

Las neuronas son células muy polarizadas y están formadas por un solo axón y varias dendritas, lo que garantiza el flujo direccional de la información en el sistema nervioso. Las dendritas reciben las señales entrantes, mientras que los axones las transmiten a las células diana. A fin de abordar la cuestión crítica en neurobiología de cómo las neuronas adquieren esta polaridad, el proyecto financiado con fondos europeos SortAx se centra en el papel de los endosomas. Los investigadores están estudiando el mecanismo por el que los endosomas clasifican las proteínas y las transportan al axón. Los resultados no solo aportarán conocimientos fundamentales sobre la biología de las neuronas, sino que también ayudarán a comprender cómo estos procesos conducen a enfermedades neurodegenerativas como la enfermedad de Alzheimer.

Objetivo

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.