Neuroinflammation and histone H3 citrullination are increased in X-linked Dystonia Parkinsonism post-mortem prefrontal cortex

Neurobiol Dis. 2020 Oct;144:105032. doi: 10.1016/j.nbd.2020.105032. Epub 2020 Jul 31.


Neuroinflammation plays a pathogenic role in neurodegenerative diseases and recent findings suggest that it may also be involved in X-linked Dystonia-Parkinsonism (XDP) pathogenesis. Previously, fibroblasts and neuronal stem cells derived from XDP patients demonstrated hypersensitivity to TNF-α, dysregulation in NFκB signaling, and an increase in several pro-inflammatory markers. However, the role of inflammatory processes in XDP patient brain remains unknown. Here we demonstrate that there is a significant increase in astrogliosis and microgliosis in human post-mortem XDP prefrontal cortex (PFC) compared to control. Furthermore, there is a significant increase in histone H3 citrullination (H3R2R8R17cit3) with a concomitant increase in peptidylarginine deaminase 2 (PAD2) and 4 (PAD4), the enzymes catalyzing citrullination, in XDP post-mortem PFC. While there is a significant increase in myeloperoxidase (MPO) levels in XDP PFC, neutrophil elastase (NE) levels are not altered, suggesting that MPO may be released by activated microglia or reactive astrocytes in the brain. Similarly, there was an increase in H3R2R8R17cit3, PAD2 and PAD4 levels in XDP-derived fibroblasts. Importantly, treatment of fibroblasts with Cl-amidine, a pan inhibitor of PAD enzymes, reduced histone H3 citrullination and pro-inflammatory chemokine expression, without affecting cell survival. Taken together, our results demonstrate that inflammation is increased in XDP post-mortem brain and fibroblasts and unveil a new epigenetic potential therapeutic target.

Keywords: Citrullination; Neuroinflammation; X-linked Dystonia Parkinsonism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Autopsy
  • Cell Survival
  • Chemokines / drug effects
  • Chemokines / metabolism
  • Citrullination* / drug effects
  • Dystonic Disorders / metabolism*
  • Dystonic Disorders / pathology
  • Female
  • Fibroblasts / drug effects
  • Genetic Diseases, X-Linked / metabolism*
  • Genetic Diseases, X-Linked / pathology
  • Gliosis / metabolism
  • Gliosis / pathology
  • Histones / drug effects
  • Histones / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Leukocyte Elastase / metabolism
  • Male
  • Microglia / metabolism
  • Microglia / pathology
  • Middle Aged
  • Ornithine / analogs & derivatives
  • Ornithine / pharmacology
  • Peroxidase / metabolism
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / pathology
  • Protein-Arginine Deiminase Type 2 / metabolism
  • Protein-Arginine Deiminase Type 4 / metabolism


  • Chemokines
  • Histones
  • N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
  • Ornithine
  • Peroxidase
  • Leukocyte Elastase
  • PADI2 protein, human
  • PADI4 protein, human
  • Protein-Arginine Deiminase Type 2
  • Protein-Arginine Deiminase Type 4

Supplementary concepts

  • Dystonia 3, Torsion, X-Linked