Spatio-temporal control of autophagy in neurons: functions and roles in diseases. – NeuroPhagy

*Context:
The ability of cells to effectively and efficiently maintain the regulation and modulation of protein biogenesis and turnover plays a key role in cellular growth, function and development. Autophagy has become one of the most studied degradative pathways that cells utilize to achieve this proteostatic balance. Sustaining cell homeostasis, this “self-digestion” machinery is essential for normal physiological functions. Moreover, its contribution to the pathogenicity of various diseases has placed autophagy as one of the most attractive target for therapy in human. In neuron, autophagosome biogenesis occurs at the axonal tip, but also in the soma and dendrites in neurons. However, the functional relevance of this compartmentalization in neurons remains elusive, and current autophagy-based therapies mostly lack specificity and may be deleterious, as a consequence of the multiple-step nature of autophagy maturation. In neurodegenerative diseases, this aspect if particularly relevant, as growing evidences reveal the roles of mutated genes in different steps of the autophagy pathway.

*Objectives:
The NeuroPhagy project has the ambition to uncover an important, yet poorly understood aspect: the spatio-temporal dynamics of autophagy in the neuron. Investigated in health, the modes of regulation and roles of autophagy dynamics in neurons will be deepened by studying gigaxonin, a regulator of autophagy activity that is essential for neuronal integrity across the entire nervous system. Coupling this fundemental knowledge on neuronal functions in vitro with physiology of the nervous system in vivo, we aim to understand the autophagy-driven mechanisms underlying health and driving dysfunctions in disease, and design novel therapeutic avenues for neurodegenerative disorders.

Combining neurobiology, mathematic modelling, chemistry and physiology, our project propose to address four main axes: WP1) Define the spatio-temporal dynamics of autophagy in neurons & mechanisms of control; WP2) Determine the roles and mechanisms of autophagy in neuron development; WP3) Characterize the physiological functions of autophagy in the nervous system; WP4) Provide a proof-of-concept for the targeting of autophagy dynamics as a therapeutic avenue for neurodegenerative diseases.

*Innovation:
NeuroPhagy aims to pinpoint conserved mechanisms and control of autophagy dynamics accross neuronal tissues and has the potential to identify therapeutic hits that can be of benefit to several neurodegenerative disease in the future.