Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Protein disulfide isomerase-immunopositive inclusions in patients with Alzheimer disease. 2055 Sep 46

Amyloid plaques and neurofibrillary tangles are the major pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles are composed of filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Derlin proteins are a family of proteins that are conserved in all eukaryotes, in which they function in endoplasmic reticulum-associated degradation. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins in the luminal space of the endoplasmic reticulum. In this study, we found that derlin-1 and PDI were colocalized in neurofibrillary tangles in the brain of patients with Alzheimer's disease. Derlin-1 and PDI may work as partners to avoid the accumulation of unfolded proteins in Alzheimer's disease. Furthermore, we found that derlin-1 was immunopositive for neurofibrillary tangles and upregulated in Alzheimer's disease and that derlin-1 may play an important role in endoplasmic reticulum-associated degradation during the pathogenesis of Alzheimer's disease. We hypothesize that derlin-1 was upregulated to avoid the aggregation of unfolded proteins. Despite the upregulation of derlin-1, the functions of chaperone proteins and Alzheimer tau protein were lost and these proteins were also accumulated. Finally, they were involved in neurofibrillary tangles. These results suggest that derlin-1 may be associated with endoplasmic reticulum stress in neuronal cells in Alzheimer's disease.
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PMID:Derlin-1-immunopositive inclusions in patients with Alzheimer's disease. 2262

Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological characteristics of Alzheimer's disease (AD). NFTs are composed of tubular filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature of AD is excessive generation of nitric oxide (NO). Protein disulfide isomerase (PDI) is a chaperon protein located in the endoplasmic reticulum (ER). It was recently reported that NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. In addition, we previously reported the presence of PDI-immunopositive NFTs in AD. Here, we found that protein disulfide isomerase P5 (P5), which is a member of the PDI protein family, was co-localized with tau in NFTs. To our knowledge, this is the first report of P5-immunopositive inclusion in AD. Furthermore, we showed that S-nitrosylated P5 was present and the expression level of P5 was decreased in AD brains compared with that of control brains. We also demonstrated that the knock-down of PDI or P5 by siRNA could affect the viability of SH-SY5Y cells under ER stress. Previously, the observation of S-nitrosylated PDI in AD was reported. NO may inhibit P5 by inducing S-nitrosylation in the same manner as PDI, which inhibits its enzymatic activity allowing protein misfolding to occur in AD. The accumulation of misfolded proteins induces ER stress and may cause apoptosis of neuronal cells through S-nitrosylation and down-regulation of PDI and P5 in AD.
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PMID:Protein disulfide isomerase P5-immunopositive inclusions in patients with Alzheimer's disease. 2403 32