Examining the role of neuronal proteolipid proteins in Neurodegeneration

This PhD project will investigate novel mechanisms of neurodegeneration arising from the neuronal expression of myelin genes. Proteolipid proteins (PLP) are best known for their function in mature oligodendrocytes where they play a key role in the formation of compact myelin. However, novel, soma-restricted isoforms of PLP (sr-PLP) are also expressed by specific populations of CNS neurons, including those in the brain stem (Miller et al., 2009) and striatum (Fulton et al., 2011). Although the function of neuronal PLP proteins is unclear, evidence from human and rodent studies suggests a role for neuronal PLP in neurodegeneration. First, duplication of the PLP1 gene drives neurodegeneration in regions of the human CNS (Sima et al., 2009) known to exhibit neuronal PLP in the rodent CNS. Importantly, these PLP1 duplications cause neurological disease, most notably Pelizaeus-Merzbacher Disease (PMD), where clinical symptoms include quadriparesis, seizures, respiratory impairments, and cognitive dysfunction. Second, rodent models bearing PLP mutations accumulate abnormal sr-PLP in brain stem neurons leading to neuronal dysfunction and lethal ventilator responses (Miller et al., 2003). Whether neurodegeneration arises indirectly following excessive accumulations of PLP in oligodendrocytes and myelin (Anderson et al., 1998), or directly from excessive deposition in neurons remains to be determined. Answering this question, and identifying the cellular mechanisms underpinning PLP driven neurodegeneration, could help to guide novel therapies for neurological disorders involving the PLP1 gene. To answer this question we will test the hypothesis that overexpression of sr-PLP induces accumulations of sr-PLP in sensitive neuronal populations, triggering apoptosis, neurodegeneration, and disruption of neurological function.

By joining this exciting project you can help to test this hypothesis in experiments involving transgenic rat models of PMD, Cre/LoxP mouse lines, and in vitro cell models. Your project will take place within Birmingham’s Oligodendrocytes and Myelin Research Group (www.birmingham.ac.uk/oligodendrocytes) where you will use cutting edge research facilities covering molecular, cellular and imaging techniques to explore the role of neuronal PLP in neurodegeneration. You will also benefit from the vibrant interdisciplinary research environment provided by the wider Neuroscience and Ophthalmology grouping, which includes scientists focussed on neuro-protection and neuro-regeneration following CNS trauma and disease.

Person Specification
Applicants should have a background in Neuroscience, biology, or biochemistry; they should have a commitment to molecular research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

Informal enquiries should be directed to Dr Daniel Fulton ([Email Address Removed])
To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.