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Dr Cahir O'Kane

Abstract:

Maintaining the structure and function of axons as long as 1m requires a lot of engineering, the importance of which is revealed in diseases where it goes wrong – e.g. hereditary spastic paraplegia (HSP), which shows preferential degeneration of longer spinal cord axons. Identifying the causative disease genes helps to reveal the processes that maintain function of long axons.    Many HSP mutations affect proteins that model ER membrane curvature by inserting in one face of the membrane, hinting at an important role for ER in axon function. Axonal ER is principally smooth tubular ER, unlike rough ER sheets in neuronal cell bodies. Its length and continuity, from dendrites through cell body and axons to presynaptic terminals, liken it to a "neuron-within-a-neuron", which might potentially conduct signals through neurons, independent of action potentials, but faster than microtubule-based transport.    We use Drosophila to study the mechanisms of organisation of axonal ER. We have developed markers for it, ways to look at it in fixed and live preparations, and at the effects of mutant genotypes on it. At least one Drosophila HSP protein is important for its organisation in longer but not in shorter axons. A number of areas are possible for a PhD, including (1) ultrastructural topology and continuity of ER network organisation in wildtype and HSP mutant axons; (2) comprehensively testing requirements for Drosophila HSP genes, and identifying new genes, in axonal ER organisation; (3) testing the requirement for ER in axonal function and signaling.

References:

  1. NC O’Sullivan, TR Jahn, E Reid, CJ O’Kane (2012) Reticulon-like-1, the Drosophila ortholog of the Hereditary Spastic Paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of distal motor axons. Hum Mol Gen 21:3356-65.    
  2. C Blackstone, CJ O’Kane, E Reid (2011) Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci 12:31-42.    
  3. X Wang, RC Shaw, HTH Tsang, E Reid, CJ O'Kane* (2007) Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules. Nature Neuroscience 10:177-85.

Dr Cahir O'Kane

Dr Cahir O'Kane
Department of Genetics
Office Phone: 01223 333177