Professor Sean Sweeney

In neurons, the endosome regulates signals controlling synapse growth. Appropriate regulation of synaptic growth is a key mechanism in refining the fidelity of synaptic communication. We work with the larval neuromuscular junction of Drosophila as a model glutamatergic synapse to identify endosomal related signaling events occurring in human pathological conditions. In parallel we use primary neurons to explore and confirm mechanisms identified in our Drosophila model

Many neurodegenerative diseases show abnormal function of endosomal compartments. My previous work has suggested that in one form of neurodegenerative disease, a childhood dementia, endosomal perturbation leads to an excessive growth of the synapse most likely due to the failure to regulate growth signals appropriately. Using this model we have identified oxidative stress as a major signal driving synapse overgrowth. We have also recently identified, with our collaborator Matthias Landgraf of the Department of Zoology, Cambridge, a critical control of synapse growth and function by the reactive oxygen species H2O2.

A current focus of the lab is the perturbed endosome found in Frontotemporal Dementia (FTD) and Amyotrophic Sclerosis. Both of these conditions can exist in a genetic spectrum where mutations in one gene can cause either FTD or ALS.  A number of the mutant genes that cause FTD-ALS are found to encode endosomal or phagosomal proteins. We have used our Drosophila model of FTD to identify factors regulating progression of the disease and we are now building up a picture of the cellular events happening in synapses when they are affected by this condition. We have identified a pro-apoptotic signal mediated by ‘Plenty-of-SH3s’ (POSH) activated in a form of FTD-ALS. This apoptotic switch is mediated by the endosome to manipulate the early endosomal compartment in the neuron, while activating a JNK-AP1 mediated cell death.

We aim to identify events in neurons caused by mutations in FTD-ALS related genes leading to pathological progression of the condition. From this point, we can target therapeutic interventions at the ‘pathological signalling’ events that contribute to neuronal death to develop treatments for FTD-ALS.