Multiple sclerosis (MS) is a complex disease of the human central nervous system (CNS) involving the patchy destruction of the myelin sheath. Previous studies have found a consistent biochemical change in MS normal appearing white matter (NAWM) i.e. the increased citrullination of myelin basic protein (MBP) resulting in decreased myelin compaction. This process is facilitated by the enzyme family of peptidylarginine deiminases (PADs), of which PAD2 and PAD4 are expressed in mouse and human brain white matter. Therefore, we propose the inhibition of PAD enzymes would reverse protein hypercitrullination and represents a potential treatment for MS. Treatment with 2-chloroacetamidine (2CA), an active site inhibitor of PAD, attenuated diseases in four independent mouse models of MS associated with decreased PAD activity level, normalized peptidylcitrullination, and improved myelin morphology. Therefore, protein hypercitrullination may be a basic mechanism implicated in both neurodegenerative and autoimmune models of MS.

Multiple sclerosis (MS) is a complex disease of the human central nervous system (CNS) involving the patchy destruction of the myelin sheath. Previous studies have found a consistent biochemical change in MS normal appearing white matter (NAWM) i.e. the increased citrullination of myelin basic protein (MBP) resulting in decreased myelin compaction. This process is facilitated by the enzyme family of peptidylarginine deiminases (PADs), of which PAD2 and PAD4 are expressed in mouse and human brain white matter. Therefore, we propose the inhibition of PAD enzymes would reverse protein hypercitrullination and represents a potential treatment for MS. Treatment with 2-chloroacetamidine (2CA), an active site inhibitor of PAD, attenuated diseases in four independent mouse models of MS associated with decreased PAD activity level, normalized peptidylcitrullination, and improved myelin morphology. Therefore, protein hypercitrullination may be a basic mechanism implicated in both neurodegenerative and autoimmune models of MS.