title: Protein disulfide isomerase immunopositive glial cytoplasmic inclusions in patients with multiple system atrophy.
abstract: BACKGROUND
  Glial cytoplasmic inclusions (GCIs) are the pathological hallmarks of multiple system atrophy (MSA) and α-synuclein is abnormally deposited in GCIs. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins by catalyzing the disulfide interchange reaction, which is the rate-limiting step during protein folding in the luminal space of the endoplasmic reticulum (ER). Nitric-oxide-induced (NO-induced) S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response in neurodegenerative diseases.
  
  
  METHODS
  Postmortem brain specimens from five patients with MSA and five normal control brains were utilized in this immunohistochemical study.
  
  
  RESULTS
  We found GCIs positive for anti-PDI antibody in the brain of patients with MSA. In addition, we observed colocalization of α-synuclein and leucine-rich repeat kinase 2 (LRRK2) with PDI in GCIs. As LRRK2 immunoreactivity is associated with one of the earliest oligodendrocytic abnormalities in MSA, colocalization of LRRK2 and PDI in GCIs may be a link to the ER stress of glial cells in the early stages of MSA.
  
  
  CONCLUSIONS
  In MSA, NO may inhibit PDI by inducing S-nitrosylation, which inhibits its enzymatic activity and thus allows protein misfolding to occur.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Honjo
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000368:Aged; D001921:Brain / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology / Q000648:ultrastructure*; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000648:ultrastructure; D011180:Postmortem Changes; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D019704:Protein Disulfide-Isomerases