Regulation of ALS-Associated SOD1 Mutant SUMOylation and Aggregation by SENP and PIAS Family Proteins.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease specific to motor neurons. Pathogenic mutations in an ALS-associated gene encoding superoxide dismutase 1 (SOD1) have been identified in familial ALS (fALS) cases. SOD1 with fALS-linked mutations is prone to form cytotoxic aggregates that cause cellular dysfunction. We previously demonstrated that the modification of SOD1 by small ubiquitin-like modifier (SUMO) 3 enhances the aggregation of fALS-linked SOD1 mutants. SUMOylation is a reversible post-translational modification targeting lysine residues. SUMO conjugation is mediated by the enzymes E1, E2, and E3, and deconjugation is catalyzed by deSUMOylation enzymes. To understand the process of SOD1 aggregation, we examined the involvement of protein inhibitor of activated STAT (PIAS) family and sentrin-specific protease (SENP) family proteins in the SUMOylation of SOD1 mutants. We found that all four types of PIAS family proteins, E3 ligase of SUMOylation, increased SUMOylation of SOD1 mutants. Among three SENP family proteins tested, deSUMOylation enzymes, SENP1, exhibited the most efficient deconjugation effect. In co-expression experiments, PIASy and SENP1 increased and decreased the number of cells exhibiting SOD1-mutant aggregation, respectively, confirming the effect of these enzymes on SOD1 aggregation. These findings suggest that regulation of SUMOylation affects the pathogenesis of ALS.

Alteration of global protein SUMOylation in neurons and astrocytes in response to Alzheimer's disease-associated insults.

SUMOylation, a post-translational modification of lysine residues by small ubiquitin-like modifier (SUMO) proteins, has been implicated in the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD), and in neuron- and astrocyte-specific physiological functions. Global SUMOylation is increased in the AD mouse brain in the pre-plaque-forming stage but returns to wild-type levels in the plaque-bearing stage. To clarify the reason for the transient change in SUMOylation, we analyzed the alteration of global SUMOylation induced by AD-associated cytotoxic stimuli in neurons and astrocytes individually. In neurons, amyloid ß42 oligomers induced some but not significant increase in levels of SUMO1-modified proteins. Both hydrogen peroxide and glutamate significantly reduced SUMO1-modified protein levels. These changes were more prominent in neurons than in astrocytes. The opposite effect of Aß and oxidative/excitotoxic stimuli on SUMO1 modification may cause the pathological stage-associated change in the level of SUMO-modified proteins in the AD mouse brain.