Involvement of peptidylarginine deiminase-mediated post-translational citrullination in pathogenesis of sporadic Creutzfeldt-Jakob disease

Abstract

Peptidylarginine deiminases (PADs)-mediated post-translational citrullination processes play key roles in protein functions and structural stability through the conversion of arginine to citrulline in the presence of excessive calcium concentrations. In brain, PAD2 is abundantly expressed and can be involved in citrullination in disease. Recently, we have reported pathological characterization of PAD2 and citrullinated proteins in scrapie-infected mice, but the implication of protein citrullination in the pathophysiology in human prion disease is not clear. In the present study, we explored the molecular and biological involvement of PAD2 and the pathogenesis of citrullinated proteins in frontal cortex of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We found increased expression of PAD2 in reactive astrocytes that also contained increased levels of citrullinated proteins. In addition, PAD activity was significantly elevated in patients with sCJD compared to controls. From two-dimensional gel electrophoresis and MALDI-TOF mass analysis, we found various citrullinated candidates, including cytoskeletal and energy metabolism-associated proteins such as vimentin, glial fibrillary acidic protein, enolase, and phosphoglycerate kinase. Based on these findings, our investigations suggest that PAD2 activation and aberrant citrullinated proteins could play a role in pathogenesis and have value as a marker for the postmortem classification of neurodegenerative diseases.

Peptidylarginine deiminase and protein citrullination in prion diseases

“…Recent studies have demonstrated that accumulated citrullinated proteins and abnormal activation of peptidylarginine deiminase 2 (PAD2) may play a role in the pathogenesis of prion diseases. 4,5 In addition, citrullinated proteins including glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and several newly identified proteins were found in prion disease and other neurodegenerative diseases. [4][5][6] PADs and citrullination.…”

“…4,5 In addition, citrullinated proteins including glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and several newly identified proteins were found in prion disease and other neurodegenerative diseases. [4][5][6] PADs and citrullination. The post-translational citrullination process is defined as the modification of an arginine residue to a citrulline residue in proteins, and this process is mediated by calcium (Ca 2+ )-dependent PAD enzymes (Fig.…”

“…Increased PAD expression and protein citrullination are commonly observed in several neurodegenerative diseases, including MS, AD, optic glaucoma and Parkinson disease, and in psoriasis, rheumatoid arthritis (RA) and cancer. [4][5][6][7]20,[31][32][33][34] In AD patients, the abnormal accumulation of citrullinated proteins and increased PAD2 expression are seen in the hippocampus, where vimentin and GFAP have been identified as PAD substrates. 6 Citrullinated proteins have also been observed in the cytoplasm of the substantia nigra dopamine neurons in Parkinson disease patients.…”

“…Astrocyte-specific GFAP is one of the most susceptible substrates of PAD2, thereby citrullinated forms of GFAP are abundantly detected in patients with multiple sclerosis (MS), Alzheimer disease (AD) and prion diseases. [4][5][6]14 Citrullinated GFAP has been shown to induce the disassembly of the intermediate filament. 15 PAD2-transgenic mice develop astrocyte and microglial activation, MBP citrullination and myelin loss.…”

La désimination ou citrullination

“…L'augmentation du taux de protéines citrullinées et la surexpression de Pad2 dans le cerveau de souris infectées par la protéine scrapie (souche ME7) tendent à prouver l'implication de cet isotype dans les maladies neurodégénératives à prions [16]. Tout récemment, une expression accrue de PAD2 et une augmentation de la désimination ont effectivement été démontrées chez l'homme dans des cas sporadiques de la maladie de Creutzfeldt-Jakob [17]. PAD2 et des taux anormalement élevés de désimination ont également été observés au niveau du nerf optique dans des cas de glaucome ou dans les cellules épithéliales des capsules de Bowman du rein lors du développement d'une néphropathie expérimentale (pour revue voir [6]).…”