Investigating the role of membrane traffic in neuronal survival

Defects in membrane traffic can occur with age leading to neuronal loss and cognitive dysfunction. The pathogenic signals arising from this membrane trafficking dysfunction are not understood. A good model for understanding the interface between ageing and endosomal dysfunction is Frontotemporal Dementia (FTD) which is a major cause of early onset dementia. Recently FTD has been placed in a disease spectrum with Amyotrophic Lateral Sclerosis (ALS or Motorneuron Disease) pointing to the importance of maintaining efficient membrane traffic for neuronal survival. Using a Drosophila model of endosomal dysfunction related to FTD, we have identified novel conserved molecules and signaling processes contributing to disrupted neural function and neuronal death (West et al., (2015) J. Cell Biol. 208: 931-47, Lu et al., (2013) Mol Cell, 52:264-271, Ahmad et al., (2009) PNAS 106: 12168-71). Novel candidate genes from our screen appear to be involved in membrane traffic processes and synapse growth regulation. We have identified a novel transmembrane protein that when mutant contributes to FTD/ALS progression via dysregulation of synaptic growth signalling and activation of innate immunity.

We aim to characterise the function and subcellular localisation of this novel protein using a combination of Drosophila genetics, and neuronal cell culture. We will then move to a genetic analysis of gene function to dissect a role for this protein in the progression of FTD/ALS and neuronal survival. The student will work in the Evans lab studying the role of this novel protein using an in vitro tissue culture and high resolution imaging approach, and in the Sweeney lab using Drosophila genetics to uncover the cross talk between synaptic growth signals and apoptosis. We are looking for an ambitious and hard working student for this cutting edge project. The student will gain experience in tissue culture, high-resolution imaging, molecular biology, CAS9/CRISPR genome engineering and functional genetics.