Summary of Research
Research in the Wishart laboratory is aimed at understanding the cellular and molecular processes which underpin the development and stability of the nervous system in health and disease, with a more specific focus on the biology of the neuron.
It is accepted that the neuron can be compartmentalized (grossly speaking) with respect to both form and function into three units: the cell body (or soma and associated dendrites), the axon and the synapse. It is also known that stability of the axon and synapse can be affected independently of one another.
Synapses are of special interest to us as it is becoming increasingly accepted that they are a primary pathological target in a number of neurodegenerative conditions, including but by no means limited to; Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and motor neuron diseases. That is to say, synapses go first and the rest of the neuron follows. As age increases the susceptibility to many of these neurodegenerative conditions, the ever increasing life expectancy of current society means that the costs associated with neurodegenerative diseases are only going to escalate over the coming years. It is therefore critical that we develop a clearer understanding of the mechanisms which underpin healthy development and stability of synapses and the regulators of altered synaptic/neuronal vulnerability.
In order to address these points we combine anatomical knowledge with high resolution imaging and biochemical/molecular biological techniques in vivo and in vitro to identify the key players and tease apart the mechanisms involved in these processes.
Wishart TM, Parson SH, Gillingwater TH. 2006. Synaptic vulnerability in neurodegenerative disease. J Neuropathol Exp Neurol. 65(8):733-9. PMID: 16896307
Wishart TM, Paterson JM, Short DM, Meredith S, Robertson KA, Sutherland C, Cousin MA, Dutia MB, Gillingwater TH. 2007. Differential proteomics analysis of synaptic proteins identifies potential cellular targets and protein mediators of synaptic neuroprotection conferred by the slow Wallerian degeneration (Wlds) gene. Mol Cell Proteomics. 6(8):1318-30. PMID: 17470424
Wishart TM, Pemberton HN, James SR, McCabe CJ, Gillingwater TH. 2008. Modified cell cycle status in a mouse model of altered neuronal vulnerability (slow Wallerian degeneration; Wlds). Genome Biol. 9(6):R101. PMID: 18570652
Kielar C, Wishart TM, Palmer A, Dihanich S, Wong AM, Macauley SL, Chan CH, Sands MS, Pearce DA, Cooper JD, Gillingwater TH. 2009. Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. Hum Mol Genet. 18(21):4066-80. PMID: 19640925
Wishart TM, Huang JP, Murray LM, Lamont DJ, Mutsaers CA, Ross J, Geldsetzer P, Ansorge O, Talbot K, Parson SH, Gillingwater TH. 2010. SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy. Hum Mol Genet. 19(21):4216-28. PMID: 20705736
Eaton et al. 2013. Total Protein Analysis as a Reliable Loading Control for Quantitative Fluorescent Western Blotting. PLoS One, Vol. 8, No. 8, e72457, 30.08.2013
Wishart et al. 2014. Dysregulation of ubiquitin homeostasis and beta-catenin signaling promote spinal muscular atrophy. Journal of Clinical Investigation. 124, 4, p. 1821-1834