Understanding myelin may offer therapeutic benefits
Multiple sclerosis, Guillian-Barré syndrome and neuropathies related to diabetes and cancer chemotherapy produce debilitating effects—difficulty moving, fatigue and numbness, to name a few.
These progressive, degenerative disorders share another trait in common: they all show evidence of having lost some of the nervous system’s natural protection, known as myelin. Formed as an insulator to wrap around nerve cells, myelin protects their functioning and survival. It is essential for rapidly conducting electrical signals to muscles.
When myelin breaks down or is destroyed, a process called demyelination, the impact can be significant and permanent.
“If you lose myelin structure, you lose the normal function of the nervous system. It affects motor skills and you can have pain,” says Haesun A. Kim, associate professor in the Department of Biological Sciences at Rutgers-Newark. Kim and her laboratory are looking for biological signals that trigger demyelination. “We think there are actual signals that tell myelin-forming cells to break down the myelin.”
“We’re trying to identify the mechanism,” she adds. “Our hope is that once we identify the signal, we can target how to prevent it from happening. That’s a long-term goal.”
Kim’s group has worked for several years on exploring myelin formation and loss in the peripheral nervous system or PNS. These nerves are found outside the brain and spinal cord, which comprise the central nervous system or CNS.
A 2012 study published by Kim and her colleagues in The Journal of Neuroscience looked at the molecular mechanisms at work in causing myelin breakdown when an enzyme—a protein kinase—is activated after peripheral nerve damage. Kim’s group has an on-going project showing that the kinase signal functions in the CNS as well.
She and her laboratory also have investigated growth factor signals, finding that a soluble form of a growth factor helps myelin-forming cells function in the PNS. “We hope it will also improve myelin repair after loss,” she says.
Some work has moved into CNS processes. Kim currently is looking at what happens to myelin during traumatic brain injury (TBI). In TBI, a blow to the head causes the brain to move rapidly, hit the skull and become damaged—such as in a football injury or car accident. The movement stretches long nerve cells called axons, which carry electrical signals from neurons, nerve cells in the brain.
To find out how TBI demyelination begins, Kim is using an axon-stretching model system created by Bryan J. Pfister, an associate professor of biomedical engineering at the New Jersey Institute of Technology (NJIT). Working collaboratively with Pfister, Kim is stretching a myelinated axon culture to identify the signal causing myelin breakdown. “We want to see if we can minimize damage,” she says.
Such research keeps Kim and her laboratory actively engaged in identifying and exploring the mechanisms behind myelin changes. That may someday help those affected by neurodegenerative diseases.
“Any new finding is exciting,” she says.
Following completion of her undergraduate work in horticulture at Seoul National University in Seoul, Korea, Haesun A. Kim came to the University of Toledo in Ohio, where she received her M.S. in biology. Kim earned a Ph.D. in cell biology, neurobiology and anatomy at the University of Cincinnati. During that time, she developed her interest in exploring Schwann cells, which form myelin in the peripheral nervous system. Kim was a postdoctoral research fellow in cell biology and neurobiology at the Dana-Farber Cancer Institute, Harvard Medical School, where she investigated cell response mechanisms in nerve injury and demyelination. Arriving at Rutgers-Newark in 2004 as an assistant professor of biology, she became an active researcher and mentor to doctoral students and junior faculty. In 2010, Kim was named associate professor. She has been, or is, principal investigator for studies funded by the National Institutes of Health, New Jersey Commission on Brain Injury Research, New Jersey Commission on Spinal Cord Research, and others.
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Selected Publications (Kim and co-authors)
- Plastic Fantastic: Schwann cells and repair of the peripheral nervous system, Stem Cells Translational Medicine, Aug. 2013
- p38 MAPK activation promotes denervated Schwann cell phenotype and functions as a negative regulator of Schwann cell differentiation and myelination, The Journal of Neuroscience, May 23, 2012
- HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination, Nature Neuroscience, April 2011
- Soluble neuregulin-1 has bi-functional, concentration-dependent effects on Schwann cell myelination, Journal of Neuroscience, Vol. 30, No. 17 (2010)
- Differentiation of oligodendrocytes requires activation of mammalian target of rapamycin signaling, Journal of Neuroscience, Vol. 29, No 19 (2009)
- Schwann cell proliferation during Wallerian degeneration is not necessary for regeneration and remyelination of the peripheral nerves: axon-dependent removal of newly generated Schwann cells by apoptosis, Molecular and Cellular Neuroscience, Vol. 38, No. 1 (2008)
- E-cadherin expression in postnatal Schwann cell is induced by activation of cAMP-dependent protein kinase A pathway, Glia, Vol. 56 (2008)
- Schwann cell preparation from single mouse embryos: Analysis of neurofibromin function in Schwann cells, Methods in Enzymology, Vol. 407 (2006)
- Schwann cells from neurofibromin deficient mice exhibit activation of p21ras, inhibition of cell proliferation and morphological changes, Oncogene, 1995
- CAMP-dependent protein kinase A is required for Schwann cell growth: interactions between the cAMP and neuregulin/tyrosine kinase pathways, Journal of Neuroscience Research, 1997. 49(2): p. 236-247
- Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farnesyl protein transferase, Molecular & Cellular Biology, 1997. 17(2): p. 862-872
- Schwann cells express NDF and SMDF/n-ARIA mRNAs, secrete neuregulin, and show constitutive activation of erbB3 receptors: evidence for a neuregulin autocrine loop, Experimental Neurology, 1997. 148(2): p. 604-615
- A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1, Neuron, 2000. 26(2): p. 405-416
- Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1, Journal of Neuroscience, 2001. 21(4): p. 1110-1116
- Mouse Brain Organization Revealed through Direct Genome-scale TF expression analysis, Science, 2004, 306 (5705): p. 2255-2257
- Microanatomy of axon/glial signaling resolved in artificial sciatic nerves, Journal of Neuroscience, 2005 25: p. 3478-3487
- Primary Schwann cell cultures, 2009 Protocols for Neural Cell Cultures, 4th edition, Humana Press/Springer Media, 2000