Multiple sclerosis (MS) is a complex brain-specific disease of unknown origin. Patients afflicted with MS exhibit a progressive decline in balance, coordination and movement, as well as fatigue, muscle weakness, and visual and sensory disturbances. These hallmark symptoms are caused by degeneration of myelin, which normally forms an insulating sheath around axons to enable rapid and efficient action-potential propagation. Myelin degeneration mechanisms in MS are not known, but an emerging theory implicates enzymatic conversion of amino acid charges in myelin basic protein (MBP). In this process known as deimination, peptidylarginine deiminase (PAD) converts positive arginine residues into the neutral amino acid citrulline. Prior studies demonstrate that MS severity is associated with increased citrulline in MBP, and that hyperdeimination leads to myelin sheath destabilization. The authors have previously identified increases in PAD2 and PAD4 away from lesions in MS brains, leading to the hypothesis that PAD upregulation is an early indicator of myelin degradation in MS.

In this study, extra copies of the rat PAD2 gene were introduced into the mouse genome to create a transgenic model of human MS. PAD2-overexpressing mice exhibited abnormal gait, hind-limb weakness, and deficits in proprioception, balance and coordination. CNS tissue analysis revealed white matter lesions and nude and hypomyelinated axons. Additionally, lesion sites had increased numbers of astrocytes, as seen in MS and MS-like diseases. The demyelination and neurological deficits were more severe in homozygous PAD2 mice than heterozygotes, indicating a dose-dependent effect of PAD2 overexpression. The authors also observed an increase in PAD4 expression in the transgenic mice, suggesting that PAD2 and PAD4 operate in the same pathway to produce the observed phenotypes.

This study provides in vivo evidence that PAD2 overexpression increases levels of citrulline in MBP and, consequently, triggers myelin destabilization. This confirms and extends previous data suggesting that the PAD-deimination pathway is important in the maintenance of myelin integrity. The PAD2 mouse described here is a novel model of demyelinating disease. Given the fact that PAD levels are increased in regions proximal to MS brain lesions, this animal model may be useful in studying the intervention of demyelination in MS. Furthermore, this work highlights the therapeutic potential of targeting PAD in demyelination disorders.

2008