The mechanism controlling sorting and axonal retrograde transport in neurons. (360G-Wellcome-107116_Z_15_Z)

Neurons have unique morphologies, which are maintained by transport events allowing precise communication over long distances. Fast axonal transport constitutes the backbone of these trafficking pathways and is required for neuronal development and survival. Accordingly, several neurodegenerative diseases are associated with deficits in axonal transport, suggesting a causal role for axonal transport dysfunction in disease pathogenesis. Multiple evidence link fast axonal transport and neuronal homeostasis, yet the mechanisms responsible for long-term transport and sorting of physiological ligands, such as neurotrophins and their receptors, are still unclear. Our overall aim is therefore to define: What are the molecular mechanisms controlling cargo uptake and sorting along the axonal transport route? We uncover an essential role for nidogens, key components of the synaptic basement membrane, in the uptake and axonal transport of tetanus neurotoxin (TeNT), and clinical tetanus. Bas ed on our findings that TeNT exploits a trafficking route used by neurotrophins for their long-range transport and signalling, this proposal aims to uncover the role of nidogens in axonal retrograde transport and neuronal survival. Using a combination of biochemistry, cell biology and intravital imaging and taking advantage of our ability to analyse axonal transport in-vitro and in-vivo, we will address the following questions: i) Do nidogens undergo axonal retrograde transport and trans- synaptic transfer in neurons? ii) What is the nature of the receptor complex targeting nidogens to this route? iii) Which signals modulate axonal transport of nidogens? iv) What is the physiological function of nidogens undergoing axonal transport?