Identifying regulators of synaptic vulnerability and novel therapeutic targets in Motor Neurone Disease

The Background: Synapses are an early pathological target in a wide variety of neurodegenerative conditions. We have previously demonstrated that targeting the mechanisms resident in synaptic compartments is sufficient to alter the response of the entire neuron to a wide range of neurodegeneration inducing insults ranging from injury through to genetically encoded diseases such as the childhood Motor Neurone Disease (MND) spinal muscular atrophy (SMA).
The Plan: We have multiple molecular data sets including “state-of-the-art” proteomic profiles of degenerating synaptic compartments in multiple neurodegenerative paradigms from “healthy” through to terminal time points. Briefly, we propose to carry out a comparative morphological screen of candidates derived from our extensive molecular datasets to identify those with the ability to moderate the neuronal perturbations characteristic of two distinct forms of MND - a childhood onset form (SMA) and an adult onset form (ALS - Amyotrophic Lateral Sclerosis) in Drosophila. Selected candidates which successfully moderate disease induced morphological alterations will be screened with proteomic tools to map out the resulting consequences to the downstream molecular cascades. This approach will allow the identification of pharmacologically manipulable candidates which may prove effective across a range of MND’s.
The output: This combined molecular-genetic approach will enable elucidation of the molecular cascades responsible for regulating neuronal stability in MND, and ultimately identifying novel therapeutic targets which will likely garner interest and investment from industry.

Prerequisites
Biomedical or neuroscience background. Familiarity with Drosophila, imaging and/or mass spectrometry would be beneficial but not essential.

The Euan MacDonald Centre will fully fund one UK/EU studentship to commence in autumn 2017. Potential applicants must contact their supervisor of choice to discuss the project before applying. The interviews with successful candidates will be held in late January 2017.