University of Dundee

*SPRINT-MND/MS PhD Programme* Targeting O-GlcNAcylation of periaxin in Charcot-Marie-Tooth type neuropathies

Protein O-GlcNAcylation is a post-translational modification that is emerging as being neuroprotective by “shielding” proteins involved in neurodegenerative proteinopathies (e.g. [1]). The van Aalten lab is studying the biological and molecular mechanisms underpinning this modification using a combination of biochemistry, structural biology and mouse/Drosophila genetics [2,3,4]. Neurodegenerative diseases are increasingly recognised as not necessarily neuronal cell autonomous [5]. Schwann cells (SCs), the myelinating glia of the peripheral nervous system, support axonal survival and function. Genetic abnormalities leading to SC dysfunction affect their ability to provide this support and maintain axon integrity. The Brophy lab has recently discovered that Periaxin (PRX), an SC myelin protein whose mutation causes inherited neuropathy in humans, is site-specifically O-GlcNAc modified [5]. PRX lacking O-GlcNAcylation is mislocalized within the myelin sheath of these mutant animals. Furthermore, phenotypes of an SC-specific OGT knockout and Prx-deficient mice are very similar, suggesting that PRX O-GlcNAcylation is crucial for myelin maintenance and axonal integrity. In this PhD project we will explore the effects of mutating out, or permanently installing, periaxin O-GlcNAc using novel technology developed in the van Aalten lab. In addition, we will explore the ability of an O-GlcNAcase hypomorphic mouse or O-GlcNAcase inhibitors (both available in the van Aalten lab) to rescue neuropathies observed in models of Charcot-Marie-Tooth type disease available in the Brophy lab. The end result of this project will be genetic and chemical validation of increasing O-GlcNAcylation on periaxin as a potential new avenue towards future treatment of neurological disease.

References

1: Wang AC, Jensen EH, Rexach JE, Vinters HV, Hsieh-Wilson LC. Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration. Proc Natl Acad Sci U S A. 2016 Dec 12. pii: 201606899.

2: Kapuria V, Röhrig UF, Bhuiyan T, Borodkin VS, van Aalten DM, Zoete V, Herr W. Proteolysis of HCF-1 by Ser/Thr glycosylation-incompetent O-GlcNAc transferase:UDP-GlcNAc complexes. Genes Dev. 2016 Apr 15;30(8):960-72.

3: Mariappa D, Zheng X, Schimpl M, Raimi O, Ferenbach AT, Müller HA, van Aalten DM. Dual functionality of O-GlcNAc transferase is required for Drosophila development. Open Biol. 2015 Dec;5(12):150234.

4: Pathak S, Alonso J, Schimpl M, Rafie K, Blair DE, Borodkin VS, Schüttelkopf AW, Albarbarawi O, van Aalten DM. The active site of O-GlcNAc transferase imposes constraints on substrate sequence. Nat Struct Mol Biol. 2015 Sep;22(9):744-50.

5: Hunter, G., R.A. Powis, R.A. Jones, E.J.N. Groen, H.K. Shorrock, F.M. Lane, Y. Zheng, D.L. Sherman, P.J. Brophy* and T.H. Gillingwater*. Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy. Hum. Mol. Gen. 25, 2853-2861.

6: Kim S, Maynard JC, Sasaki Y, Strickland A, Sherman DL, Brophy PJ, Burlingame AL, Milbrandt J. Schwann Cell O-GlcNAc Glycosylation Is Required for Myelin Maintenance and Axon Integrity. J Neurosci. 2016 Sep 14;36(37):9633-46.

Prerequisites

BSc biochemistry/neurobiology with honours project and/or MSc project experience in the neurobiology space. Experience with general biochemical techniques. Experience with (primary) cell culture and animal models desirable but not essential.

Please contact your intended supervisor to discuss the project and your suitability for it before submitting your application.

Application link:  http://www.edneurophd.ed.ac.uk/genetics/targeting-o-glcnacylation-periaxin-charcot-marie-tooth-type-neuropathies%232017-sprint-dun2

The project is a part of SPRINT-MND/MS, a new Scotland-wide PhD scheme for research into motor neurone disease and multiple sclerosis. Projects, encompassing a wide range of topics including laboratory, clinical, and social sciences, are available at Aberdeen, Dundee, Edinburgh, Glasgow and St Andrews Universities. This exciting initiative provides a great opportunity for budding researchers in any field related to MND or MS to join Scotland’s network of world-leading scientists and health professionals. Find more information here: http://www.edneurophd.ed.ac.uk/sprint-mndms-phd-programme

Eligibility