title: 4-Hydroxynonenal induces persistent insolubilization of TDP-43 and alters its intracellular localization.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of motor neurons. TDP-43 has been found to be a major component of ubiquitin-positive inclusions in ALS. Aberrant TDP-43, which is found in inclusions, is phosphorylated and is re-distributed from the nucleus to the cytoplasm. Alterations of TDP-43 protein, particularly insolubilization/aggregation and cytosolic distribution are thought to be involved in the pathogenesis of ALS. Levels of 4-hydroxynonenal (HNE), a marker of oxidative stress, have been reported to be elevated in sporadic ALS patients. However, the effects of HNE on TDP-43 are unclear. In this study, we found that HNE treatment of cells causes insolubilization, phosphorylation, and partial cytosolic localization of TDP-43. HNE-induced cytosolic TDP-43 was diffusely localized and only a small proportion of TDP-43 localized to stress granules, which are transient structures. HNE-induced TDP-43 insolubilization and phosphorylation were even observed 24 h after washout of HNE. We also showed that the cysteine residues of TDP-43 are responsible for HNE-induced insolubilization of TDP-43. Our results indicate that HNE can cause biochemical changes of TDP-43, which resemble the aberrant alterations of this protein in ALS, and suggest that upregulation of HNE could be a risk factor for ALS.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Chihana
authors.initials: C
authors.lastname: Kabuta
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan; Department of Electrical Engineering and Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kono
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: kabuta@ncnp.go.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kabuta
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012995:Solubility
chemical_list: D000447:Aldehydes; D015415:Biomarkers; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; C000598624:TARDBP protein, human; C027576:4-hydroxy-2-nonenal
keywords: ALS; HNE; Oxidative stress; TDP-43