title: ApoSOD1 lacking dismutase activity neuroprotects motor neurons exposed to beta-methylamino-L-alanine through the Ca2+/Akt/ERK1/2 prosurvival pathway.
abstract: Amyotrophic lateral sclerosis (ALS) is a severe human adult-onset neurodegenerative disease affecting lower and upper motor neurons. In >20% of cases, the familial form of ALS is caused by mutations in the gene encoding Cu,Zn-superoxide dismutase (SOD1). Interestingly, administration of wild-type SOD1 to SOD1G93Atransgenic rats ameliorates motor symptoms through an unknown mechanism. Here we investigated whether the neuroprotective effects of SOD1 are due to the Ca2+-dependent activation of such prosurvival signaling pathway and not to its catalytic activity. To this aim, we also examined the mechanism of neuroprotective action of ApoSOD1, the metal-depleted state of SOD1 that lacks dismutase activity, in differentiated motor neuron-like NSC-34 cells and in primary motor neurons exposed to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA). Preincubation of ApoSOD1 and SOD1, but not of human recombinant SOD1G93A, prevented cell death in motor neurons exposed to L-BMAA. Moreover, ApoSOD1 elicited ERK1/2 and Akt phosphorylation in motor neurons through an early increase of intracellular Ca2+concentration ([Ca2+]i). Accordingly, inhibition of ERK1/2 by siMEK1 and PD98059 counteracted ApoSOD1- and SOD1-induced neuroprotection. Similarly, transfection of the dominant-negative form of Akt in NSC-34 motor neurons and treatment with the selective PI3K inhibitor LY294002 prevented ApoSOD1- and SOD1-mediated neuroprotective effects in L-BMAA-treated motor neurons. Furthermore, ApoSOD1 and SOD1 prevented the expression of the two markers of L-BMAA-induced ER stress GRP78 and caspase-12. Collectively, our data indicate that ApoSOD1, which is devoid of any catalytic dismutase activity, exerts a neuroprotective effect through an early activation of Ca2+/Akt/ERK1/2 pro-survival pathway that, in turn, prevents ER stress in a neurotoxic model of ALS.
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Petrozziello
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.
authors.forename: Agnese
authors.identifier: 0000-0001-5054-4098
authors.initials: A
authors.lastname: Secondo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Tedeschi
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Esposito
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.
authors.forename: MariaJosè
authors.initials: M
authors.lastname: Sisalli
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Scorziello
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Via Sergio Pansini 5, Naples, Italy.|Fondazione IRCCS SDN, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D000599:Amino Acids, Diamino / Q000633:toxicity*; D000818:Animals; D001059:Apoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000087522:Cyanobacteria Toxins; D000091342:Endoplasmic Reticulum Chaperone BiP; D005419:Flavonoids / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology; D000072105:Superoxide Dismutase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000599:Amino Acids, Diamino; D001059:Apoproteins; D002118:Calcium; D000087522:Cyanobacteria Toxins; D000091342:Endoplasmic Reticulum Chaperone BiP; D005419:Flavonoids; D006360:Heat-Shock Proteins; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D000072105:Superoxide Dismutase-1; D014212:Tretinoin; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C001824:beta-N-methylamino-L-alanine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one