Protein homeostasis is essential for the wellbeing of several cellular systems. Post-translational modifications (PTM) coordinate various pathways in response to abnormal aggregation of proteins in neurodegenerative disease states. In the presence of accumulating misfolded proteins and toxic aggregates, the small ubiquitin-like modifier (SUMO) is associated with various substrates, including chaperones and other recruited factors, for refolding and for clearance via proteolytic systems, such as the ubiquitin-proteasome pathway (UPS), chaperone-mediated autophagy (CMA) and macroautophagy. However, these pathological aggregates are also known to inhibit both the UPS and CMA, further creating a toxic burden on cells. This review suggests that re-routing cytotoxic aggregates towards selective macroautophagy by modulating the SUMO pathway could provide new mechanisms towards neuroprotection.

α-Synuclein inclusion bodies are a pathological hallmark of several neurodegenerative diseases, including Parkinson’s disease, and contain aggregated α-synuclein and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin and the small ubiquitin-like modifier, SUMO-1. Cell culture and animal model studies suggest that misfolded, aggregated α-synuclein is actively translocated via the cytoskeletal system to a region of the cell where other factors that help to lessen the toxic effects can also be recruited. SUMO-1 covalently conjugates to various intracellular target proteins in a way analogous to ubiquitination to alter cellular distribution, function and metabolism and also plays an important role in a growing list of cellular pathways, including exosome secretion and apoptosis. Furthermore, SUMO-1 modified proteins have recently been linked to cell stress responses, such as oxidative stress response and heat shock response, with increased SUMOylation being neuroprotective in some cases. Several recent studies have linked SUMOylation to the ubiquitin-proteasome system, while other evidence implicates the lysosomal pathway. Other reports depict a direct mechanism whereby sumoylation reduced the aggregation tendency of α-synuclein, and reduced the toxicity. However, the precise role of SUMO-1 in neurodegeneration remains unclear. In this review, we explore the potential direct or indirect role(s) of SUMO-1 in the cellular response to misfolded α-synuclein in neurodegenerative disorders.

An array of cellular responses attempt to defend cells from the formation of protein aggregates in neurodegenerative diseases, including Parkinson’s disease (PD), by removing or detoxifying the aggregated proteins. SUMO-1 participates in the autophagy response to protein aggregates via SUMOylation of lysosomal Hsp90. In this study, the influence of two specific chemical inhibitors of the SUMOylation E1 enzyme, ginkgolic acid and anacardic acid, as well as spectinomycin, on a cellular model of PD was determined. Depolarization of SH-SY5Y cells with 50 mM KCl was used to induce calcium influx and a-synuclein (a-syn) and its relation to autophagy under SUMO-1 inhibition, aggregation analogous to that observed in PD. SUMO inhibitors at various concentrations were added to these cells to determine the clearance of aggregated protein. Immunofluorescence studies were performed and cell counting methods were incorporated. Student’s t test was performed to determine statistical relevance. Immunofluorescence (IF) revealed a decrease in the frequency of a-syn aggregates under both ginkgolic acid (p<0.01) and anacardic acid (p<0.1) treatments at 10µM. It also revealed that there was a significant reduction of punctate co-localization of SUMO-1 and lysosomal marker, Cathepsin D, under ginkgolic acid (p<0.001) and anacardic acid (p<0.01) treatments at 10µM. Furthermore, there was significant up-regulation of LC3 (p<0.05), marking autophagosomes, under ginkgolic acid treatments from 3µM to 10µM and under anacardic acid treatments from 6µM to 10µM. Similar results were in experiments under the influence of spectinomycin. The findings suggest that inhibition of the SUMOylation pathway disrupts SUMO-1 co-localization with lysosomes. The increased levels of LC3-positive autophagosomes and decline in the frequency of protein aggregates in cell culture suggest that macroautophagy may have a key role in mediating protein aggregate clearance in response to SUMO-1 inhibition. Further experiments are utilizing Western blots to validate the IF results obtained.