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.

MATERIALS AND 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: Yasuyuki Honjo, Hidefumi Ito, Tomohisa Horibe, Ryosuke Takahashi, Koji Kawakami
• Journal: The International journal of neuroscience (Int J Neurosci) Vol. 121 Issue 10 Pg. 543-50 (Oct 2011) ISSN: 1563-5279 [Electronic] England
• PMID: 21689057 (Publication Type: Journal Article)

Chemical References

• alpha-Synuclein
• LRRK2 protein, human
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Protein Serine-Threonine Kinases
• Protein Disulfide-Isomerases

Topics

• Aged
• Brain (pathology)
• Humans
• Inclusion Bodies (enzymology)
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Microscopy, Immunoelectron
• Middle Aged
• Multiple System Atrophy (pathology)
• Neuroglia (pathology, ultrastructure)
• Neurons (metabolism)
• Oligodendroglia (metabolism, ultrastructure)
• Postmortem Changes
• Protein Disulfide-Isomerases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• alpha-Synuclein (metabolism)