| Increased levels of nitrosative stress intracellularly within the endoplasmic reticulum is a key factor involvled in the pathogenesis of both Parkinson's (PD) and Alzheimer's (AD) diseases. Previous in-vitro studies in our lab showed that increased levels of nitrosative stress lead to aggregation of misfolded proteins and formation of Lewy Bodies, the main biomarker of PD and AD diseases. Although this was mainly through nitrosylation of Protein Disulfide Isomerase (PDI), the chief endoplasmic reticulum (ER) resident oxidoreductase chaperone responsible for maturation of disulfide-bond-containing proteins, we demonstrate in this project that increased levels of nitrosative stress has an additional direct effect on maturation of disulfide-bond containing proteins. Importantly, we demonstrate that the maturation of disulfide-containing proteins under conditions mimicking nitrosative stress can be rescued by the naturally occurring ellagic acid. Our data reveals that ellagic acid can serve as a lead prophylactic agent in searching for small molecules that can prevent against oxidative/nitrosative stress-related neurodegenerative diseases. |
