Molecular links between synaptic membrane trafficking and the onset of neurodegenerative diseases

The molecular mechanisms underlying the onset of neurodegeneration remain obscure, and the elucidation of these mechanisms is one of the key goals of biomedicine. Recent studies revealed novel properties of several proteins central to control synaptic vesicle (SV) cycling.

Besides having well-defined roles in SV membrane trafficking, these proteins may switch their path following post-translational modifications and join the autophagy-lysosome pathway or become involved in the regulation of mitochondrial functions.

Our previous work and preliminary studies strongly suggest that alterations in these proteins may lead to the onset of neurodegeneration in a number of pathological conditions, including Parkinson´s disease (PD).

In this project, we propose to elucidate the functions of endophilin-A proteins and their interactors in order to understand how lack of endophilin, and consequently defects in SV cycling and membrane trafficking, lead to neurodegeneration.

Moreover, we are aiming at elucidating the molecular mechanisms for onset of early pathology, which may be of direct relevance for PD: (1) the role of endophilin and its interactors in liquid-liquid phase separation and onset of pathological alpha-synuclein containing protein aggregates at synapses; (2) the molecular link between endophilin-A network and Lmx1B in the autophagy-lysosome pathway;(3) effects of mutations in the endophilin-A interactor E3-ubiquitin ligase Parkin in dopaminergic neurons.