h2g2 The Hitchhiker's Guide to the Galaxy: Earth Edition

Friday, October 24, 2003


SGH team under Dr Xiao makes important discovery

by Tan Hui Leng
[email protected]

A Singapore medical research team has made a breakthrough discovery that could finally lead to a cure for multiple sclerosis (MS).
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After four years of painstaking effort, the 15-person team at Singapore General Hospital's (SGH) department of clinical research has found the key to myelin-sheath formation in humans.
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The team, led by senior research scientist Dr Xiao Zhi Cheng, beat more than 100 other research groups around the world as they unlocked the secret to what could offer hope not just for MS sufferers, but also people with spinal-cord injuries, such as actor Christopher Reeves.
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MS is a motor neuron disorder characterised by the destruction of the myelin sheath, or fatty insulation, that surrounds axons, or nerve fibres, in the brain and spinal cord. Many MS sufferers go through life with some form of disability.
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The SGH team, which collaborated with laboratories in five countries, found that the myelin sheath is formed when the molecules, "notch" and "contactin", reach a point called the paranode on the axon.
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This pathway has never been discovered and can be applied to produce drugs that could induce myelin shealth formation in multiple sclerosis patients.
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The team's discovery was the cover story of the Oct 17 issue of Cell, a prestigious US-based molecular biology magazine.
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SingHealth, the public healthcare group to which SGH belongs, has patented the discovery and is looking into its commercialisation. There is a potential market of 2.5 million MS patients worldwide.
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"The target would be to develop treatments that could mimic "notch" or "contactin" function, as that would trigger myelin-sheath formation," said Dr Xiao.
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Medical discoveries such as this typically take more than 10 years to translate into commercial products, because a comprehensive series of tests and trials is needed to ensure consumer safety.
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Typically, MS is diagnosed in adults between 20 and 40 years, with more women than men being affected. All they can hope for now is drugs that help manage symptoms such as pain.
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Trained as a medical doctor, Dr Xiao has been conducting research in molecular biology for 20 years and has published about 20 papers.
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This is the first time that a paper of his has been selected for publication in Cell.
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For a summary of Dr Xiao's paper,
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log on to http://www.cell.com

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Axon-derived molecules are temporally and spatially required as positive or negative signals to coordinate oligodendrocyte differentiation. Increasing evidence suggests that, in addition to the inhibitory Jagged1/Notch1 signaling cascade, other pathways act via Notch to mediate oligodendrocyte differentiation. The GPI-linked neural cell recognition molecule F3/contactin is clustered during development at the paranodal region, a vital site for axoglial interaction. Here, we show that F3/contactin acts as a functional ligand of Notch. This trans-extracellular interaction triggers γ-secretase-dependent nuclear translocation of the Notch intracellular domain. F3/Notch signaling promotes oligodendrocyte precursor cell differentiation and upregulates the myelin-related protein MAG in OLN-93 cells. This can be blocked by dominant negative Notch1, Notch2, and two Deltex1 mutants lacking the RING-H2 finger motif, but not by dominant-negative RBP-J or Hes1 antisense oligonucleotides. Expression of constitutively active Notch1 or Notch2 does not upregulate MAG. Thus, F 3/contactin specifically initiates a Notch/Deltex1 signaling pathway that promotes oligodendrocyte maturation and myelination.