Giampietro Schiavo : Molecular Neuro-Pathobiology

Goals

The goal of our laboratory is to build up a functional map of the organelles responsible for the endocytic sorting and axonal transport of neurotrophin receptors and selected virulence factors in neurons. By studying the basic mechanisms controlling membrane dynamics, we aim to provide new insights into how neurons and other cells control the uptake, sorting and degradation of ligands at nerve terminals in health and disease.

Unique among other cells, neurons must communicate over distances spanning almost the size of an organism. Fast axonal transport constitutes the backbone of long-distance communication in neurons, functionally connecting distal areas with events occurring within the soma and vice versa. Importantly, it regulates the spatio-temporal pattern of receptor stimulation by trophic and morphogenetic factors. In spite of its physiological relevance, characterisation of the mechanisms controlling the targeting of specific ligands to specific axonal transport routes remains in its infancy.

In the last few years, we have intensified our efforts to characterise the molecular machinery regulating endocytosis of neurotrophin receptor complexes at nerve terminals and their sorting towards the axonal retrograde transport route. The identification of the constituents of these carriers and their characterisation has allowed us to demonstrate an essential role for the small GTPases Rab5 and Rab7 in the biogenesis of these organelles and their fast transport along microtubules. Comparative analysis of axonal signalling endosomes isolated from different neuronal subtypes at early and late stages of their maturation is now allowing us to create a physical map of these organelles and define the mechanism of endosomal maturation at molecular level. We have recently integrated this approach with siRNA screens using neurons derived from mouse embryonic stem (ES) cells. This approach has allowed us to identify molecular motors and adaptors required for endocytic trafficking in neurons.