Peptidylarginine deiminase: a candidate factor in demyelinating disease

In earlier studies we demonstrated that an increase in the relative amounts of citrullinated myelin basic protein (MBP) was found in multiple sclerosis (Moscarello et al. 1994). To determine the temporal relationship between the citrullinated MBP and peptidylarginine deiminase (PAD), the enzyme responsible for deiminating arginyl residues in proteins, we studied enzyme activity, enzyme protein, PAD mRNA in a spontaneously demyelinating transgenic mouse model and we correlated the amount of PAD with citrullinated MBP. Both PAD protein as measured in an immunoslot blot method and PAD RNA were elevated. In fractionation studies we showed that the increase in PAD enzyme was due to an increase in the PAD found in membrane fractions and not the soluble PAD (PADII). From our data we concluded that up-regulation of myelin-associated PAD was responsible for the increase in citrullinated MBP in our transgenic mice prior to onset of clinical or pathological signs of demyelination. We postulate that a similar mechanism may be responsible for the increase in citrullinated MBP in multiple sclerosis.