Monash researchers claim key MS find

Monash University researchers have solved the crystal structure of the protein suspected to be the focus of the autoimmune attack that destroys the fatty insulating sheath around neurons in the brain in multiple sclerosis (MS).

Dr Jamie Rossjohn's team of Dr Hugh Reid, Dr Craig Clements and Dr Travis Beddoe in the protein crystallography unit of the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, has defined to atomic resolution the precise shape of myelin oligodendrocyte glycoprotein (MOG).

The research was recently published in the Proceedings of the National Academy of Sciences.

MOG forms a thin layer on the exterior of the myelin sheath that wraps around neurons, insulating them against current leakage as they transmit impulses.

Rossjohn said internationally renowned MS expert Dr Claude Bernard, of La Trobe University, was largely responsible for the focus of MS research shifting from the most abundant protein in the myelin sheath, myelin basic protein, to MOG.

MOG accounts for only 0.05 per cent of the total protein of the myelin sheath, and is expressed only in neurons in the central nervous system -- the brain and spinal cord -- not in the peripheral nervous system. It exists both as a monomeric and a homodimeric species in vivo.

Rossjohn said the extracellular domain of MOG resembled an immunoglobulin (Ig) domain, hinting at some normal role in the immune response. The Monash researchers have shown the molecule forms an antiparallel, head-to-tail dimer, leading them to conclude it is an adhesion factor that binds neighbouring neurons together.

In MS, the immune system attack, which involves both autoantibodies and T-cells, is directed against peptide regions partly hidden within the interface between the dimerised molecules. This suggests the MS disease process involves a breakdown in MOG's normal physiological function.

One of the occluded peptides has been shown to be strongly immunogenic in mouse and marmoset models of MS. The autoimmune attack causes severe inflammation, eroding the myelin sheath and exposing regions of the enclosed axon, or nerve body.

The immune system normally ignores MOG as a 'self' antigen, but in some individuals, it directs unfriendly fire at it, causing MS.

Rossjohn said the MOG protein was highly conserved, not just within humans but across mammal species, so antigenic variation between individuals does not explain MS.

He said the next step would be to use surface plasmon resonance, and site-directed mutagenesis of the native protein, to determine where, and how tightly, autoreactive antibodies bind to the protein.

With chemists at the Victorian College of Pharmacy, Rossjohn's team will be looking for synthetic drugs to block the autoantibody attack of MOG, thereby quelling the immune response.

Rossjohn said solving the protein's crystal structure had meant an overseas trip to use the third generation synchrotron at the Argonne National Laboratory in Chicago.

He said each overseas synchrotron trip was a major logistical exercise, and that he was waiting for the day when Australia's first synchrotron lit up over the road from Monash University.