Molecules affecting myelin stability: A novel hypothesis regarding the pathogenesis of multiple sclerosis
Mastronardi FG, Moscarello MA.
Structural Biochemistry and Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
In this Mini-Review we present a new hypothesis in support of the neurodegenerative theory as a mechanism for the pathogenesis of multiple sclerosis (MS). The pathogenesis of MS results from changes in two distinct CNS compartments. These are the "myelin" and "nonmyelin" compartments.
The myelin compartment is where primary demyelination, amidst attempts at remyelination, is superseded in the CNS by ongoing disease. Recent evidence obtained via magnetic resonance imaging and spectroscopy techniques supports the view that the normal-appearing white matter (NAWM) in the MS brain is altered. Several biochemical changes in NAWM have been determined. These include the cationicity of myelin basic protein (MBP) as a result of the action of peptidyl argininedeiminase (PAD) activity converting arginyl residues to citrulline. The accompanying loss of positive charge makes myelin susceptible to vesiculation and MBP more susceptible to proteolytic activity. An increase of MBP autocatalysis in the MS brain might also contribute to the generation of immunodominant epitopes. Accompanying the destruction of myelin in the myelin compartment is the activation of astrocytes and microglia. These contribute to the inflammatory response and T-cell activation leading to autoimmunity.
The complex environment that exists in the demyelinating brain also affects the "nonmyelin" compartment. The inappropriate up-regulation of molecules, including those of the Jagged-1-Notch-1 signal transduction pathway, affects oligodendrocyte precursor cell (OPC) differentiation. Other effectors of oligodendrocyte maturation include stathmin, a microtubule-destabilizing protein, which prevents healing in the demyelinating brain.
The hypothesis we present suggests a therapeutic strategy that should 1) target the effectors within the myelin compartment and 2) enable resident OPC maturation in the nonmyelin compartment, allowing for effective repair of myelin loss. The net effect of this new therapeutic strategy is the modification of the disease environment and the stimulation of healing and repair. (c) 2005 Wiley-Liss, Inc.
http://www.ncbi.nlm.nih.gov/entrez/quer ... s=15704220
The hypothesis is possible, but not necessarily novel. One of the people I worked with at the University of Florida got a grant a few years ago to study peptidyl arginine deiminase with regards to lupus, although
he works on all autoimmune diseases. He was interested primarily with regards to histones since those are positively charged with alot of arginine and lysine. But he would look at other proteins too.
Arginine and lysine are two postively charged amino acids when they are incorporated into a protein so they add to the overall positive charge of a protein like MBP or histones. Peptidyl arginine deiminase (PAD) is an enzyme that converts the arginine to citrulline, like the article says, which reduces the positive charge at that site and the overall charge in the protein.
The question is: why does the PAD get out of control? Perhaps there is a mutation or epigenetic change in the PAD gene promoter so that it is expressed more frequently. Perhaps there is a mutation in the sequence so that it does not get degraded as rapidly as it normally would. Or perhaps it is more lax in what it modifies and how it recognizes its target sites due to mutations. Perhaps there are extra alleles active that are not normally active. (An allele is a copy of the gene, a gene can have several copies or alleles spread around the genome, on different chromosomes for example. For some genes only one allele is active and the others are kept silent with the potential to become active under abnormal or special conditions.)
Maybe I'll contact my friend and see what he has come up with. At one point he said he was getting something interesting. I think there could be other possibilities for the overall change in myelin charges but PAD should certainly be studied.
this article links to PAD2/4
under certain conditions, ROS plus PAD may cause citrullination
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