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Characterising the human Amyotrophic Lateral Sclerosis (ALS) synaptic proteome

Project Description

Amyotrophic Lateral Sclerosis (ALS) is caused by the breakdown of upper and lower motor neurons leading to the progressive weakness and atrophy of muscle, often resulting in respiratory failure and death within a few years of diagnosis. It is the most common form of Motor Neuron Disease (MND), yet we still do not have any effective treatments, mostly due to our lack of a unifying theory of disease pathogenesis.

Synapse loss is a critical early step in disease, occurring at each connection point throughout the motor system; the brain, spinal cord and neuromuscular junction (NMJ). However, synapse loss is not restricted to the motor system. We have recently shown in the human ALS brain that synapse loss associates with a decline in cognitive function, a feature that is found in up to half of all ALS patients. The next big challenge is to identify the synaptic pathways and proteins that are disrupted in ALS, which may reveal novel therapeutic targets, which are desperately needed for this disease.

To do this, we are initiating a large unbiased proteomic screen of human brain synaptic fractions from ALS and control brains. Synaptic fractions will be enriched from the homogenised brain samples and proteins extracted before being sent to the FingerPrints Proteomics facility in Dundee for protein identification. The ALS cohort will be divided by their cognitive and genetic status, which will highlight proteins within the synapse that have changed in expression between control and ALS, thus identifying disrupted pathways and protein networks.

Under the guidance of Dr Tom Wishart from the University of Edinburgh, the PhD student will screen the proteomic dataset for novel pathways and proteins for experimental follow up. Once identified, these hits will be validated with human brain tissue using a plethora of imaging and molecular biology techniques. These include the high-resolution imaging technique, array tomography. We are one of only two labs in the world with access to human brain that has been processed for this technique, providing the student with a unique opportunity to study human ALS brain at the synaptic level.

Furthermore, from the same cases used for the proteomics study we can search for clinical correlates with identified synaptic proteomic changes. Finally, to assess the role of identified proteins in disease, the PhD student will be involved in the establishment of in vitro and potentially in vivo model systems.

This is a unique opportunity to work in an exciting new lab and help discover novel protein networks involved in ALS synaptic vulnerability.

This project will be based in the new lab of Dr Chris Henstridge at the University of Dundee’s School of Medicine, with a proposed start date of 1 October 2019. Please contact Dr Chris Henstridge with any enquiries ()

To apply please send a cover letter, curriculum vitae and two references to:

Funding Notes

Funding is provided for up to three years and includes a stipend of approx £15,000 per annum and university PhD fees at current UK/EU rates.

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