title: Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis.
abstract: Here we report that chromogranins, components of neurosecretory vesicles, interact with mutant forms of superoxide dismutase (SOD1) that are linked to amyotrophic lateral sclerosis (ALS), but not with wild-type SOD1. This interaction was confirmed by yeast two-hybrid screen and by co-immunoprecipitation assays using either lysates from Neuro2a cells coexpressing chromogranins and SOD1 mutants or lysates from spinal cord of ALS mice. Confocal and immunoelectron microscopy revealed a partial colocalization of mutant SOD1 with chromogranins in spinal cord of ALS mice. Mutant SOD1 was also found in immuno-isolated trans-Golgi network and in microsome preparations, suggesting that it can be secreted. Indeed we report evidence that chromogranins may act as chaperone-like proteins to promote secretion of SOD1 mutants. From these results, and our finding that extracellular mutant SOD1 can trigger microgliosis and neuronal death, we propose a new ALS pathogenic model based on the toxicity of secreted SOD1 mutants.
authors.affiliation: Department of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l' Université Laval, 2705 boulevard Laurier, Sainte-Foy, Quebec G1V 4G2, Canada.
authors.forename: Makoto
authors.initials: M
authors.lastname: Urushitani
authors.forename: Attila
authors.initials: A
authors.lastname: Sik
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D016475:3T3 Cells; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D053379:Chromogranin A; D002864:Chromogranins / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D007395:Interneurons / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D008861:Microsomes / Q000201:enzymology; D018832:Molecular Chaperones / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D061988:Proteasome Inhibitors; D017510:Protein Folding; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013347:Subcellular Fractions / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D053379:Chromogranin A; D002864:Chromogranins; D018832:Molecular Chaperones; D061988:Proteasome Inhibitors; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1