MS is caused by loss of myelin in the central nervous system (CNS) which includes the brain and spinal cord. It is the oligodendrocytes, the cells that generate the insulating myelin coat, that are lost. A crucial therapeutic challenge after a de-myelinating event is to identify ways to promote re-myelination by surviving oligodendrocytes. Dr Simon Murray & Dr Junhau Xiao have identified that Brain Derived Neurotrophic Factor (BDNF), a growth factor expressed in the CNS, positively regulates myelination in isolated cells grown in the laboratory. This project will use a genetic approach to investigate the role BDNF plays in myelination in laboratory models. Analysis of how BDNF promotes myelination may provide new therapeutic strategies for the treatment of MS.
Dr Murray and Dr Xiao have achieved a huge amount with the work in this project. Firstly, they have shown that BDNF plays a key role in myelination during normal brain development. Dr Murray & Dr Xiao have also investigated the role of BDNF in myelination in both the CNS and peripheral nervous system (PNS; consisting of the nerve fibres throughout the body) using cells grown in the laboratory.
In the CNS, BDNF promotes myelination by enhancing the oligodendrocyte maturation and growth processes. In the PNS, BDNF promotes myelination by increasing the nerve cells responsiveness to myelination. Interestingly, BDNF can also inhibit myelination in the PNS, depending on the molecules that are present on the nerve cell surface. Dr Murray & Dr Xiao have also shown for the first time, that the precursor protein from which BDNF is derived, independently promotes myelination and identified the mechanisms and signalling between cells that controls this.
Most excitingly, the researchers are now looking at pharmacological blocks for the important molecules and their interactions identified in this work. Hopefully, this will contribute to the development of potential therapies of MS in future.
This groundbreaking work has also provided the preliminary data to attract further funding from the Federal Government’s National Health and Medical Research Council (2010) of $460,000 In 2011, they were also successful in obtaining a NMSS project grant of US$540,000 over three years. Dr Murray and Dr Xiao have also produced six publications with another underway (marked with an asterisk below).
J. Xiao, A.H. Ferner, A.W. Wong, M. Denham, T.J. Kilpatrick, S.S. Murray. (2012) Extracellular signal-regulated kinase 1/2 signaling promotes oligodendrocyte myelination in vitro. The Journal of Neurochemistry 122(6):1167-80.
A.W. Wong, J. Xiao, D. Kemper, T.J. Kilpatrick, S.S. Murray. (2013) Oligodendroglial expression of TrkB independently regulates myelination and progenitor cell proliferation. The Journal of Neuroscience 33(11):4947-57.
Xiao J, Ferner A, Wong A, Willingham M, Denham M, Kilpatrick T, Murray S. Erk2 signalling in oligodendrocytes regulate myelination.
Binder MD, Xiao J, Kemper D, Ma GZM, Murray SS, Kilpatrick TJ. (2011) Gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone-induced demyelination PLoS One 6(3): e17727
Xiao J, Wong AW, Willingham MW, van den Buuse M, Kilpatrick TJ, Murray SS. (2010) Brain-Derived Neurotrophic Factor Promotes Central Nervous System Myelination via a Direct Effect upon Oligodendrocytes. NeuroSignals 18(3):186-202
Xiao J, Wong AW, Willingham MW, Kaasinen S, Hendry I, Howitt J, Putz U, Barrett G, Kilpatrick TJ, Murray SS. (2009) BDNF exerts contrasting influence on peripheral myelination of NGF and BDNF-dependent DRG neurons. The Journal of Neuroscience 29: 4016-4022
Wong A, Wellington M, Xiao J, Kilpatrick TJ, Murray SS. (2008) The Neurotrophin Receptor Homolog-2 regulates Nerve Growth Factor signalling. Journal of Neurochemistry 106(4):1964-76
Xiao J, Kilpatrick, TJ, Murray SS. (2009) The role of neurotrophins in the regulation of myelin development. Neurosignals17:265–276
Xiao J, Murray SS, Hughes RA. (2012) ‘Neurotrophins in Myelination and Demyelination’, In Handbook: Neurotoxicity. Edited by Kostrzewa Richard. Springer, Heidelberg, Germany. (Book Chapter).
Updated: 06 January, 2009