Blocking brain and spinal cord damage in MS

Jae Lee

Monash Immunology and Stem Cell Laboratories, VIC

January 2013

specialisation: Neurobiology

focus area: A cure via repair and regeneration

funding type: Scholarship

project type: Investigator Led Research

Summary

The protective sheath of nerve fibres (axons), known as myelin, ensures that neural impulses are effectively transmitted. It has been long believed that MS is initiated by the body’s own immune cells, which are miss-programmed to attack myelin. However, increasing evidence suggests that MS can occur as a consequence of other targets within the nervous system that may not be specific to myelin. In fact, the initial destruction of axons can occur prior to any myelin damage occurring.

Dr Petratos’ group recently identified a protein involved in the degeneration of nerve cells and showed that the modification of this protein caused damage to axons. This project will further investigate how this modified protein is involved during the degeneration of axons and prior to clinical symptoms in a laboratory model of MS. This project will then attempt to block the modification of this protein, using novel strategies and delivery systems to the brain and spinal cord. Blocking this molecule may then prevent the later axonal damage. This specific approach may provide a new therapeutic application for preventing illness progression in people with MS.

Progress

This project has used novel analysis approaches to explore whether damage to nerve fibres could be avoided by targeting an axon growth inhibitor that has been linked with neurodegeneration. In animal models of MS, previous work from Dr Petratos’ group showed that preventing the actions of this growth inhibitor were associated with reduced degeneration of nerve fibres, and recent work undertaken by Jae Lee in this scholarship showed that this blockade was also associated with significantly less damage to the myelin surrounding the nerve fibres in this animal model. These findings provide evidence that the axon growth inhibitor is able to influence the structure of both nerve fibres and the myelin surrounding them, and this may have important implications for future treatment development in MS.

Additional work has shown that mice with MS-like illness who also lacked a gene involved in this pathway tended to show less severe disease symptoms. Further study of these mice identified that they may have specific differences in the structure of their myelin and nerve fibres compared to MS-like mice that are not lacking this gene.

Jae Lee has also completed work on the final aim which was to study the processes of myelination using human haematopoietic stem cells to produce oligodendrocyte progenitor cells. Jae Lee’s findings in this area have been very interesting and may be useful in determining new treatment options for MS. The team have recently filed for a provisional patent based on this work.

publications

  • Alshehri. B., D’Souza D. G., Lee. J. Y., Petratos S. & Richardson S. J. 2015. The diversity of mechanism influenced by transthyretin in neurobiology: development, disease and endocrine disruption. J Neuroendocrinol 2015, doi: 10.1111/jne.12271.
  • Lee. J. Y., Taghian. K. & Petratos. S. 2014. Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability? Acta Neuropathol Commun 2014, 2:97
  • Alrehaili, A., Lee. J. Y., Taghian, K., Bakhuraysah, M., Thomas, S. & Petratos, S. 2014. Microglial Mechanisms Governing Axonal Degeneration in Multiple Sclerosis: A pathological Perspective. J Neurol Neurophysiol. 2014. 5:206.
  • Litwak, S. A., Payne, N. L., Campanale, N., Ozturk, E., Lee. J. Y., Petratos, S., Siatskas, C., Bakhuraysah, M. & Bernard, C. C. 2013. Nogo-Receptor 1 Deficiency Has No Influence on Immune Cell Repertoire or Function during Experimental Autoimmune Encephalomyelitis. PLoS ONE, 8(12): e82101. doi:10.1371/journal.pone.0082101 (5-Year IF= 4.24)
  • Petratos, S. & Lee. J. Y. 2013. Stop CRMPing my style: a new competitive model of CRMP oligomerization. J Neurochem, 125, 800-2. (5-Year IF= 4.022)
  • Lee. J. Y. & Petratos. S. Multiple Sclerosis: Does Nogo Play a Role? Neuroscientist, August, 2013, 19: 394-408. (5-Year IF=6.491)
  • Petratos, S., Ozturk, E., Azari, M. F., Kenny, R., Lee. J. Y., Magee, K. A., Harvey, A. R., Mcdonald, C., Taghian, K., Moussa, L., Aui, P. M., Siatskas, C., Litwak, S., Fehlings, M. G., Strittmatter, S. M. & Bernard, C. C. 2012. Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation. Brain, 135, 1794-818. (5-Year IF= 10.846)
  • Taghian, K., Lee. J. Y., & Petratos, S. 2012. Phosphorylation and Cleavage of the Family of Collapsin Response Mediator Proteins May Play a Central Role in Neurodegeneration after CNS Trauma. J Neurotrauma, 29, 1728-35 (5-Year IF= 4.062)
  • Litwak SA, Payne NL, Campanale N, Ozturk E, Lee J. Y., et al. (2013) Nogo-Receptor 1 Deficiency Has No Influence on Immune Cell Repertoire or Function during Experimental Autoimmune Encephalomyelitis. PLoS ONE 8(12): e82101. doi:10.1371/journal.pone.0082101.

Three further manuscripts are in preparation.

Updated: 20 April 2015

lead investigator

Jae Lee

supervisor

total funding

$70,000

start year

2013

duration

3 years

STATUS

Past project

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Blocking brain and spinal cord damage in MS