title: An 11-mer Amyloid Beta Peptide Fragment Provokes Chemical Mutations and Parkinsonian Biomarker Aggregation in Dopaminergic Cells: A Novel Road Map for "Transfected" Parkinson's.
abstract: Amyloid beta (Aβ) aggregation is generally associated with Alzheimer's onset. Here, we demonstrate that incubation of dopaminergic SH-SY5Y cells with an Aβ peptide fragment (an 11-mer composed of residues 25-35; Aβ (25-35)) results in elevated intracellular nitrosative stress and induces chemical mutation of protein disulfide isomerase (PDI), an endoplasmic reticulum-resident oxidoreductase chaperone. Furthermore, Aβ (25-35) provokes aggregation of both the minor and major biomarkers of Parkinson's disease, namely, synphilin-1 and α-synuclein, respectively. Importantly, fluorescence studies demonstrate that Aβ (25-35) triggers colocalization of these Parkinsonian biomarkers to form Lewy-body-like aggregates, a key and irreversible milestone in the neurometabolic cascade leading to Parkinson's disease. In addition, fluorescence assays also reveal direct, aggregation-seeding interactions between Aβ (25-35), PDI and α-synuclein, suggesting neuronal pathogenesis occurs via prion-type cross-transfectivity. These data indicate that the introduction of an Alzheimer's-associated biomarker in dopaminergic cells is proliferative, with the percolative effect exercised via dual, independent, Parkinson-pathogenic pathways, one stress-derived and the other prion-like. The results define a novel molecular roadmap for Parkinsonian transfectivity via an Alzheimeric burden and reveal the involvement of PDI in amyloid beta induced Parkinson's.
authors.affiliation: Department of Chemistry, ‡Department of Biological Sciences, Bioscience Research Building, Border Biomedical Research Center, the Cytometry, Screening and Imaging Core Facility, University of Texas at El Paso , El Paso, Texas 79968, United States.
authors.forename: Parijat
authors.initials: P
authors.lastname: Kabiraj
authors.affiliation: Department of Chemistry, ‡Department of Biological Sciences, Bioscience Research Building, Border Biomedical Research Center, the Cytometry, Screening and Imaging Core Facility, University of Texas at El Paso , El Paso, Texas 79968, United States.
authors.forename: Jose Eduardo
authors.initials: JE
authors.lastname: Marin
authors.affiliation: Department of Chemistry, ‡Department of Biological Sciences, Bioscience Research Building, Border Biomedical Research Center, the Cytometry, Screening and Imaging Core Facility, University of Texas at El Paso , El Paso, Texas 79968, United States.
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramirez
authors.affiliation: Department of Chemistry, ‡Department of Biological Sciences, Bioscience Research Building, Border Biomedical Research Center, the Cytometry, Screening and Imaging Core Facility, University of Texas at El Paso , El Paso, Texas 79968, United States.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Narayan
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D000067493:Dynamic Light Scattering; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D066263:Protein Aggregation, Pathological; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C497605:Snca protein, mouse; C498464:Sncaip protein, mouse; D051844:alpha-Synuclein; C074636:amyloid beta-protein (25-35); D049452:Green Fluorescent Proteins
keywords: Lewy body; Neurodegeneration; alpha synuclein; amyloid beta (25−35) peptide; protein disulfide isomerase; synphilin-1