title: Ellagic acid mitigates SNO-PDI induced aggregation of Parkinsonian biomarkers.
abstract: Nitrosative stress mediated S-nitrosylation (SNO) of protein disulfide isomerase (PDI), a housekeeping oxidoreductase, has been implicated in the pathogenesis of sporadic Parkinson's (PD) and Alzheimer's (AD) diseases. Previous cell line studies have indicated that SNO-PDI formation provokes synphilin-1 aggregation, the minor Parkinsonian biomarker protein. Yet no work exists investigating whether SNO-PDI induces α-synuclein aggregation, the major Lewy body constituent associated with Parkinson's pathogenesis. Here, we report that SNO-PDI formation is linked to the aggregation of α-synuclein and also provokes α-synuclein:synphilin-1 deposits (Lewy-body-like debris) normally found in the PD brain. Furthermore, we have examined the ability of a small molecule, 2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione (ellagic acid; EA) to scavenge NOx radicals and to protect cells from SNO-PDI formation via rotenone insult both, cell-based and cell-independent in vitro experiments. Furthermore, EA not only mitigates nitrosative-stress-induced aggregation of synphilin-1 but also α-synuclein and α-synuclein:synphilin-1 composites (Lewy-like neurites) in PC12 cells. Mechanistic analyses of the neuroprotective phenomena revealed that EA lowered rotenone-instigated reactive oxygen species (ROS) and reactive nitrogen species (RNS) in PC12 cells, imparted antiapoptotic tributes, and directly interfered with SNO-PDI formation. Lastly, we demonstrate that EA can bind human serum albumin (HSA). These results collectively indicate that small molecules can provide a therapeutic foothold for overcoming Parkinson's through a prophylactic approach.
authors.affiliation: Department of Chemistry, ‡Department of Biological Sciences, §Cytometry, Screening and Imaging Core Facility and Border Biomedical Research Center, The University of Texas at El Paso , El Paso, Texas 79968, United States.
authors.forename: Parijat
authors.initials: P
authors.lastname: Kabiraj
authors.forename: Jose Eduardo
authors.initials: JE
authors.lastname: Marin
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramirez
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Zubia
authors.forename: Mahesh
authors.initials: M
authors.lastname: Narayan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D004610:Ellagic Acid / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000097:blood; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C498463:Sncaip protein, rat; D051844:alpha-Synuclein; D012402:Rotenone; D004610:Ellagic Acid; D009569:Nitric Oxide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019704:Protein Disulfide-Isomerases
keywords: ER stress; Parkinson’s disease; S-nitrosylation; apoptosis; ellagic acid; human serum albumin; protein disulfide isomerase; rotenone; synphilin-1; α-synuclein