Dementia is a set of incurable, fatal diseases characterised by irreversible degeneration of the brain. One theory of its cause is the failure of intracellular transport in the axons of the neurons that compose the brain. Kinesin is a key motor transporting vital cargo along the axon. We know that this motor is a bipedal engine stepping forward along a polypeptide track but it is too small and fast for this motion to be observed using current experimental techniques. The stepping detail is therefore open to debate. This study firstly addresses the question of how kinesin steps and secondly pilots a possible method for investigating transport disruption in silico. To investigate the detail of stepping, a program has been designed and built to simulate kinesin traversing its track along a section of axon. The motor is modelled as simple, interacting agents obeying rules abstracted from known chemical and binding properties of its components. The agent-based method has proven useful and efficient on the small scale and has potential for simulating the larger and more complex system of axonal transport. This would enable investigation of transport failure in the context of finding a cure for dementia. A new model of kinesin stepping has been formulated as a consequence of performing virtual experiments using the simulation. Analysis of in vivo and in vitro experimental studies shows that the model accounts for a wide range of published results, explaining many findings. New experiments are suggested to test the model based on its falsifiable predictions. The principal conclusion of this study is that kinesin stepping is rectified Brownian motion.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:560195 |
| Date | January 2011 |
| Creators | Wilson, Richard John |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/49216/ |
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