Protein disulfide isomerase-immunopositive inclusions in patients with Alzheimer disease.
Alzheimer disease (AD) is the most common neurodegenerative disease, but there is currently no effective treatment available because the etiology or mechanism of AD is still unclear. Many neurodegenerative diseases feature inclusions, which contain accumulations of misfolded, aggregated proteins. Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological hallmarks of AD. NFTs are composed of tubular filaments, and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature is excessive generation of nitric oxide synthetase, reactive nitrogen species, and reactive oxygen species. Protein disulfide isomerase (PDI) is a member of the thioredoxin (TX) 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 (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. In this study, we found NFTs positive for anti-PDI-antibody in the brain of patients with AD. As far as we know, this is the first report of anti-PDI-antibody-immunopositive inclusions in AD. In AD, NO may inhibit PDI by inducing S-nitrosylation, which inhibits its enzymatic activity and thus allows protein misfolding to occur. Consequently, the accumulation of misfolded proteins induces ER stress. The ER stress can cause apoptosis of neuronal cells. These results suggest that PDI could be a therapeutic target to prevent ER stress in neuronal cells in AD.
Honjo
Yasuyuki
Y
Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Japan. honjyo@kuhp.kyoto-u.ac.jp
Ito
Hidefumi
H
Horibe
Tomohisa
T
Takahashi
Ryosuke
R
Kawakami
Koji
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D017209:Apoptosis; D001921:Brain / Q000473:pathology*; D006801:Humans; D016874:Neurofibrillary Tangles / Q000201:enzymology*; D058225:Plaque, Amyloid / Q000201:enzymology; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D017382:Reactive Oxygen Species; D016875:tau Proteins; D019704:Protein Disulfide-Isomerases