title: Glutaredoxin 2 prevents aggregation of mutant SOD1 in mitochondria and abolishes its toxicity.
abstract: Vulnerability of motoneurons in amyotrophic lateral sclerosis (ALS) arises from a combination of several mechanisms, including protein misfolding and aggregation, mitochondrial dysfunction and oxidative damage. Protein aggregates are found in motoneurons in models for ALS linked to a mutation in the gene coding for Cu,Zn superoxide dismutase (SOD1) and in ALS patients as well. Aggregation of mutant SOD1 in the cytoplasm and/or into mitochondria has been repeatedly proposed as a main culprit for the degeneration of motoneurons. It is, however, still debated whether SOD1 aggregates represent a cause, a correlate or a consequence of processes leading to cell death. We have exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and in the IMS (Grx1) or in the mitochondrial matrix (Grx2) as a tool for restoring a correct redox environment and preventing the aggregation of mutant SOD1. Here we show that the overexpression of Grx1 increases the solubility of mutant SOD1 in the cytosol but does not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells (SH-SY5Y) or in immortalized motoneurons (NSC-34). Conversely, the overexpression of Grx2 increases the solubility of mutant SOD1 in mitochondria, interferes with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserves mitochondrial function and strongly protects neuronal cells from apoptosis. The toxicity of mutant SOD1, therefore, mostly arises from mitochondrial dysfunction and rescue of mitochondrial damage may represent a promising therapeutic strategy.
authors.affiliation: Institute for Neuroscience CNR, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferri
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorenzo
authors.forename: Monica
authors.initials: M
authors.lastname: Nencini
authors.forename: Mauro
authors.initials: M
authors.lastname: Cozzolino
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Pesaresi
authors.forename: Cristiana
authors.initials: C
authors.lastname: Valle
authors.forename: Sara
authors.initials: S
authors.lastname: Sepe
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Carrì
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D054477:Glutaredoxins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D054477:Glutaredoxins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1