Synaptic localisation and transfer of TDP-43 in Amyotrophic Lateral Sclerosis

Synaptic localisation and transfer of TDP-43 in Amyotrophic Lateral Sclerosis

Project Code: 

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 a unifying theory of disease pathogenesis. Synapse loss has emerged as a critical early step in disease, occurring at each connection point throughout the motor system; the brain, spinal cord and neuromuscular junction (NMJ). We have recently shown that in the human ALS brain, synapse loss associates with a decline in cognitive function, which is found in up to half of all ALS patients. Furthermore, in some ALS cases we found small aggregates of the most common pathological ALS protein (pTDP-43) in synaptic terminals. Recent work has suggested that TDP-43 spreads through the brain in a predictable pattern, via synaptically connected brain regions. This gives rise to the possibility that in ALS, pTDP-43 may accumulate at the synapse to cause synaptic dysfunction and loss, before transferring to other connected cells.

To test this hypothesis, the PhD student will systematically analyse the expression of pTDP-43 in human ALS brain using the high-resolution imaging technique, array tomography. We are the only labs in the world (as far as we know) that processes human ALS tissue for this technique, providing the PhD student with a unique opportunity to access this valuable resource. This approach will allow the quantification of synaptic density in different regions of the brain and assess pTDP-43 aggregates at both pre- and post-synaptic terminals, providing a snapshot of pathology in one or both sides of the synapse. We have recently used this approach to study the transfer of alpha-synuclein in human cases of Lewy Body Dementia. Furthermore, brains from well-characterised TDP-43 mouse models will also be analysed for synaptic pTDP-43 pathology. Culture of primary neurons in microfluidic chambers will allow the student to assess the dynamic transfer of TDP-43 at the synapse. Neurons do not exist in isolation in the brain, therefore co-cultures of neurons and glial cells will be used to assess the role of glia in the transfer of TDP-43.

The student will gain experience in ultrathin tissue sectioning, high-resolution imaging of human ALS tissue, primary cell culture and various immunohistochemical techniques. While experience in any of these techniques would be an advantage, it is not essential, as full training will be provided.

Additional Project Info 
This PhD project is offered by the Euan MacDonald Centre for Motor Neurone Disease Research See The Euan MacDonald PhD Scheme here:
Primary Host Research Centre 
Secondary Host Research Centre 
Funding Status of this Project 
Deadline for Application 
Monday, 7 January, 2019
Research Area(s) 
Motor neurone disease (ALS)
Translational Neuroscience