Investigating molecular targets for remyelination
Dr Jessica Fletcher, funded by an MS Research Australia Postdoctoral Fellowship, with the support of the Trish MS Research Foundation has made significant progress over the course of her research fellowship.
· * MS is caused by the damage of myelin in the brain and spinal cord. Over time the ability of the body to repair myelin damage erodes, leading to the progression of MS symptoms.
· * Dr Fletcher undertook a fellowship to look at a naturally occurring biological pathway that promotes myelin repair using a molecule called Brain Derived Neurotrophic Factor (BDNF).
· * She identified the molecules within the myelin producing cells that lead to repair and was able to artificially modulate this pathway to promote an increase in the quantity and quality of myelin repair.
· * This project is the first step towards identifying whether the BDNF pathway may be a useful target for developing new treatments to promote myelin repair.
Dr Fletcher made significant progress over the course of her research fellowship. She has found that when a laboratory model of MS was given BDNF, Erk1/2 pathways within the myelin producing cells. In turn, this appears to enhance myelin repair, as at the same time, she discovered that more nerve cells were myelinated, and had a thicker myelin sheath. Dr Fletcher was able to show that removing this pathway within the cells stopped the myelin repair, proving that this pathway is required for myelin repair. This is the first time this has been demonstrated and these findings have been submitted for publication in scientific journals and has already been presented at national and international conferences.
To identify targets for future therapies, Dr Fletcher also performed experiments to determine which other molecules might be involved in the activity of Erk1/2. She has concentrated on the way that ERk1/2 interact with the molecules involved in regulating gene activity. She has now identified the mechanism of this interaction at a molecular level. In follow up work Dr Fletcher is determining the functional relevance of these interactions to the repair of myelin in cells grown in the laboratory. This will determine if they could be potential targets for future therapies to promote myelin repair in MS. This project is the first step towards identifying whether the BDNF pathway may be a useful target for developing new treatments to promote myelin repair and halt MS disease progression.
As a result of her work, Dr Fletcher also secured further grants from the Ian Potter Foundation, the Gordon Research Conferences, the International Society for Neurochemistry and The University of Melbourne. This research provided preliminary data for grants awarded by the ARC Discovery Project Scheme, CASS Foundation and United States Department of Defense. Dr Fletcher was awarded the 2018 Melbourne Neuroscience Institute Fellowship which will allow her to continue to this work.
Fletcher JL, Wood RJ, Nguyen J, Norman EML, Jun CMK, Biemond M, Nguyen HTH, Gonsalvez DG, Xiao J and Murray SS. Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain. Under review
Nicholson M, Wood R, Fletcher J, van den Buuse M, Murray S and Xiao J. BDNF haploinsufficiency exerts a transient and regionally different influence upon oligodendroglial cell during postnatal development. Under review
Govier-Cole AE, Wood RJ, Fletcher JL, Cate HS, Murray SS and Xiao J. Inhibiting bone morphogenetic protein-4/Type I receptors signalling promotes remyelination via potentiating oligodendrocyte differentiation. Manuscript in preparation