title: ER Protein Processing Under Oxidative Stress: Implications and Prevention.
abstract: Elevated levels of mitochondrial nitrosative stress have been associated with the pathogenesis of both Parkinson's and Alzheimer's diseases. The mechanism involves catalytic poisoning of the endoplasmic reticulum (ER)-resident oxidoreductase chaperone, protein disulfide isomerase (PDI), and the subsequent accumulation of ER-processed substrate proteins. Using a model system to mimic mitochondrial oxidative and nitrosative stress, we demonstrate a PDI-independent mechanism whereby reactive oxygen species (ROS) compromise regeneration rates of disulfide bond-containing ER-processed proteins. Under ROS-duress, the secretion-destined traffic adopts disulfide-exposed structures making the protein flux retrotranslocation biased. We also demonstrate that ROS-compromised protein maturation rates can be rescued by the polyphenol ellagic acid (EA). Our results are significant in that they reveal an additional mechanism which could promote neurodegenerative disorders. Furthermore, our data reveal that EA possesses therapeutic potential as a lead prophylactic agent against oxidative/nitrosative stress-related neurodegenerative diseases.
authors.affiliation: Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA.
authors.forename: Mahmoud F
authors.initials: MF
authors.lastname: Khalil
authors.affiliation: Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Valenzuela
authors.affiliation: Boston University School of Medicine, 72 E Concord St, Boston, MA, 02118, USA.
authors.forename: Daniella
authors.initials: D
authors.lastname: Sisniega
authors.affiliation: Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA. rskouta@utep.edu.|Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA. rskouta@utep.edu.
authors.forename: Rachid
authors.initials: R
authors.lastname: Skouta
authors.affiliation: Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA. mnarayan@utep.edu.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Narayan
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism; D002417:Cattle; D004220:Disulfides / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D018384:Oxidative Stress; D010851:Picrates / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001713:Biphenyl Compounds; D004220:Disulfides; D010851:Picrates; D017382:Reactive Oxygen Species; C004931:1,1-diphenyl-2-picrylhydrazyl; D012259:Ribonuclease, Pancreatic
keywords: Ellagic acid; Nitrosative stress; Parkinson’s disease; Protein aggregation; Protein folding; Radical scavengers