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 (SOD1^A4V, SOD1^V31A, and SOD1^G93C). 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.

Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review

“…Thus, preventing SUMOylation of SOD1 may be beneficial to limit progression of fALS. Certainly, inhibition of mutant SOD1 SUMOylation at K75 has proven a successful approach to prevent SOD1 aggregation in neuronal cells [175], and therefore underpins a rationale for translation to animal models.…”

The Roles of SUMO in Metabolic Regulation

“…This occurs through the regulation of some of the most fundamental metabolic processes, including energy and nucleotide metabolism, and permits physiological adaptation in response to cellular and environmental queues (Enserink 2015; Makhnevych et al 2009). SUMO has been implicated in complex human diseases and developmental anomalies that are also associated with nutritional and/or metabolic perturbations including Alzheimer’s disease (Dorval and Fraser 2007; Hoppe et al 2015; Lee et al 2013, 2014b; Martins et al 2016; McMillan et al 2011; Sarge and Park-Sarge 2009), Parkinson’s disease (Guerra de Souza et al 2016) (Eckermann 2013; Krumova et al 2011), type I diabetes (Li et al 2005; Wang and She 2008), familial partial lipodystrophy (Simon et al 2013), diabetes-mediated cardiovascular disease (Chang and Abe 2016), congenital heart disease (Wang et al 2011), cardiomyopathy (Kim et al 2015c; Zhang and Sarge 2008), arthritis (Yan et al 2010), amyotrophic lateral sclerosis (Dangoumau et al 2016; Foran et al 2013; Niikura et al 2014), and cleft lip and/or palate (Alkuraya et al 2006; Song et al 2008; Tang et al 2014). …”

Minimotifs dysfunction is pervasive in neurodegenerative disorders

“…Similarly, in PD, sumoylation of αSyn inhibits its aggregation [150,151]. The pathogenic fragment of HTT is sumoylated in HD, and SOD aggregation in ALS is also effected [152–155]. Pathogenic mutation of sumoylated residues in valosin‐containing protein/p97 inhibits its translocation to the nucleus, the formation of stress granules, reduction of hexamer formation, and eventually, inhibition of its clearance.…”