title: Rotenone induces neurotoxicity through Rac1-dependent activation of NADPH oxidase in SHSY-5Y cells.
abstract: Neurodegenerative diseases are attributed to impairment of the ubiquitin-proteasome system (UPS). Oxidative stress has been considered a contributing factor in the pathology of impaired UPS by promoting protein misfolding and subsequent protein aggregate formation. Increasing evidence suggests that NADPH oxidase is a likely source of excessive oxidative stress in neurodegenerative disorders. However, the mechanism of activation and its role in impaired UPS is not understood. We show that activation of NADPH oxidase in a neuroblastoma cell line (SHSY-5Y) resulted in increased oxidative and nitrosative stress, elevated cytosolic calcium, ER-stress, impaired UPS, and apoptosis. Rac1 inhibition mitigated the oxidative/nitrosative stress, prevented calcium-dependent ER-stress, and partially rescued UPS function. These findings demonstrate that Rac1 and NADPH oxidase play an important role in rotenone neurotoxicity.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Pal
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Tanner O
authors.initials: TO
authors.lastname: Monroe
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Palmieri
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Sardiello
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA. Electronic address: Rodney@bcm.edu.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D012402:Rotenone; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein
keywords: Impaired UPS; NADPH oxidase; Neurodegenerative disease; Nox; Rac1; Rotenone