Biochimica et biophysica acta. General subjects | 2021
Glucose-induced oxidative stress leads to in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells.
Abstract
BACKGROUND\nDementia places a significant burden on both patients and caregivers. Since diabetes is a risk factor for dementia, it is imperative to identify the relationship between diabetes and cognitive disorders. Protein disulfide isomerase (PDI) is an enzyme for oxidative protein folding. PDI S-nitrosylation is observed in the brain tissues of Alzheimer s disease patients. The aim of this study is to clarify the relationship between PDI S-nitrosylation and diabetes.\n\n\nMETHODS\nWe used SH-SY5Y cells cultured in high-glucose media.\n\n\nRESULTS\nS-nitrosylated PDI level increased at 7\u202fdays and remained high till 28\u202fdays in SH-SY5Y cells cultured in high-glucose media. Using PDI wild-type- or PDI C343S-expressing SH-SY5Y cells, PDI C343 was identified as the site of glucose-induced S-nitrosylation. IRE1α and PERK were phosphorylated at day 14 in the SH-SY5Y cells cultured in high-glucose media, and the phosphorylated status was maintained to day 28. To determine the effect of S-nitrosylated PDI on endoplasmic reticulum stress signaling, SH-SY5Y cells were treated with S-nitrosocystein (SNOC) for 30\u202fmin, following which the medium was replaced with SNOC-free media and the cells were cultured for 24\u202fh. Only phosphorylated IRE1α treated with SNOC was associated with PDI S-nitrosylation. Neohesperidin, a flavonoid in citrus fruits, is a natural antioxidant. The treatment with neohesperidin in the final 7\u202fdays of glucose loading reversed PDI S-nitrosylation and improved cell proliferation.\n\n\nCONCLUSION\nGlucose loading led to S-nitrosylation of PDI C343 and induced neurodegeneration via IRE1α phosphorylation.\n\n\nGENERAL SIGNIFICANCE\nThe results may be useful for designing curative treatment strategies for dementia.