Deimination in prion diseases

Abstract

Peptidylarginine deiminases (PADs) are known to be directly affected by Ca2+ homeostasis and irreversibly catalyze the posttranslational deimination (or citrullination) of peptidylarginine to peptidylcitrulline in a Ca2+-dependent manner. Over the past decade, Ca2+-dependent peptidylarginine deiminases (PADs) and deiminated proteins have emerged as key molecules in neurodegeneration and inflammatory responses associated with diseases such as multiple sclerosis, Alzheimer disease, prion disease, and rheumatoid arthritis. Prion diseases (also known as transmissible spongiform encephalopathies) are well characterized by various neurological symptoms and common histopathological features, including spongiform degeneration, reactive gliosis, neuronal loss, and the accumulation of disease-associated misfolded prion proteins (termed PrPSc) in the central nervous system. Although current knowledge of the molecular and pathological features of PAD enzymes is still limited in neurodegenerative diseases, we previously demonstrated that the upregulation of PAD2 and abnormal accumulation of deiminated proteins, which are correlated with disease progression, were found in prion disease-affected human and mouse brains. Proteomic analysis and electron immunogold labeling further revealed that a variety of deiminated proteins with increased PAD2 in infected brains were widely distributed in different subcellular compartments in neuronal and glial cells. Our recent in vivo and in vitro studies elicited altered functions of enolase as the result of citrullination; these altered functions included reduced enzyme activity, increased protease sensitivity, and enhanced plasminogen-binding affinity. Further investigation of deiminated proteins and their potential physiological and pathogenic functions in prion diseases will be useful for the development of diagnostic tools as well as potential pathogenic targets in prion diseases.