title: Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis.
abstract: Multiple sclerosis (MS) is the most common CNS-demyelinating disease of humans, showing clinical and pathological heterogeneity and a general resistance to therapy. We first discovered that abnormal myelin hypercitrullination, even in normal-appearing white matter, by peptidylarginine deiminases (PADs) correlates strongly with disease severity and might have an important role in MS progression. Hypercitrullination is known to promote focal demyelination through reduced myelin compaction. Here we report that 2-chloroacetamidine (2CA), a small-molecule, PAD active-site inhibitor, dramatically attenuates disease at any stage in independent neurodegenerative as well as autoimmune MS mouse models. 2CA reduced PAD activity and protein citrullination to pre-disease status. In the autoimmune models, disease induction uniformly induced spontaneous hypercitrullination with citrulline+ epitopes targeted frequently. 2CA rapidly suppressed T cell autoreactivity, clearing brain and spinal cord infiltrates, through selective removal of newly activated T cells. 2CA essentially prevented disease when administered before disease onset or before autoimmune induction, making hypercitrullination, and specifically PAD enzymes, a therapeutic target in MS models and thus possibly in MS.
authors.affiliation: Molecular Structure and Function, The Research Institute, Hospital For Sick Children, Toronto, ON M5G 1X8, Canada. mam@sickkids.ca
authors.forename: Mario A
authors.initials: MA
authors.lastname: Moscarello
authors.forename: Helena
authors.initials: H
authors.lastname: Lei
authors.forename: Fabrizio G
authors.initials: FG
authors.lastname: Mastronardi
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.forename: Hubert
authors.initials: H
authors.lastname: Tsui
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Cameron
authors.initials: C
authors.lastname: Ackerley
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Reinout
authors.initials: R
authors.lastname: Raijmakers
authors.forename: D Denise
authors.initials: DD
authors.lastname: Wood
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D000076342:Protein-Arginine Deiminases; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis
chemical_list: C509120:2-chloroacetamidine; D000578:Amidines; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D002956:Citrulline; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases