Rescue of ER oxidoreductase function through polyphenolic phytochemical intervention: implications for subcellular traffic and neurodegenerative disorders.
Protein disulfide isomerase (PDI), the chief endoplasmic reticulum (ER) resident oxidoreductase chaperone that catalyzes maturation of disulfide-bond-containing proteins is involved in the pathogenesis of both Parkinson's (PD) and Alzheimer's (AD) diseases. S-nitrosylation of PDI cysteines due to nitrosative stress is associated with cytosolic debris accumulation and Lewy-body aggregates in PD and AD brains. We demonstrate that the polyphenolic phytochemicals curcumin and masoprocol can rescue PDI from becoming S-nitrosylated and maintain its catalytic function under conditions mimicking nitrosative stress by forming stable NOx adducts. Furthermore, both polyphenols intervene to prevent the formation of PDI-resistant polymeric misfolded protein forms that accumulate upon exposure to oxidative stress. Our study suggests that curcumin and masoprocol can serve as lead-candidate prophylactics for reactive oxygen species induced chaperone damage, protein misfolding and neurodegenerative disease; importantly, they can play a vital role in sustaining traffic along the ER's secretory pathway by preserving functional integrity of PDI.
Pal
Rituraj
R
Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968, USA.
Cristan
Elaine A
EA
Schnittker
Karina
K
Narayan
Mahesh
M
D003474:Curcumin / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology*; D019636:Neurodegenerative Diseases / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D009637:Masoprocol; D019704:Protein Disulfide-Isomerases; D003474:Curcumin