title: Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons. Mutations in the SOD1 gene encoding the superoxide dismutase 1 are present in 15% of familial ALS cases and in 2% of sporadic cases. These mutations are associated with the formation of SOD1-positive aggregates. The mechanisms of aggregation remain unknown, but posttranslational modifications of SOD1 may be involved. Here, we report that NSC-34 motor neuronal cells expressing mutant SOD1 contained aggregates positive for small ubiquitin modifier-1 (SUMO-1), and in parallel a reduced level of free SUMO-1. CLEM (correlative light and electron microscopy) analysis showed nonorganized cytosolic aggregates for all mutations tested (SOD1A4V, SOD1V31A, and SOD1G93C). We next show that preventing the SUMOylation of mutant SOD1 by the substitution of lysine 75, the SUMOylation site of SOD1, significantly reduces the number of motor neuronal cells with aggregates. These results support the need for further research on the SUMOylation pathways, which may be a potential therapeutic target in ALS.
authors.affiliation: UMR INSERM U930, Universitx00E9; Franx00E7;ois-Rabelais, Tours, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Dangoumau
authors.forename: Sylviane
authors.initials: S
authors.lastname: Marouillat
authors.forename: Julien
authors.initials: J
authors.lastname: Burlaud Gaillard
authors.forename: Rustem
authors.initials: R
authors.lastname: Uzbekov
authors.forename: Charlotte
authors.initials: C
authors.lastname: Veyrat-Durebex
authors.forename: Hélène
authors.initials: H
authors.lastname: Blasco
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.forename: Philippe
authors.initials: P
authors.lastname: Corcia
authors.forename: Christian R
authors.initials: CR
authors.lastname: Andres
authors.forename: Patrick
authors.initials: P
authors.lastname: Vourc'h
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D003412:Cricetulus; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D017433:Protein Structure, Secondary; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation / Q000502:physiology*; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000606290:SOD1 protein, human; D025842:SUMO-1 Protein; D049452:Green Fluorescent Proteins; D000072105:Superoxide Dismutase-1; D008239:Lysine