@article{discovery10032511,
           pages = {13176--13181},
           title = {SUMOylation and ubiquitination reciprocally regulate {\ensuremath{\alpha}}-synuclein degradation and pathological aggregation},
       publisher = {National Academy of Sciences},
            note = {This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.},
          volume = {114},
         journal = {Proceedings of the National Academy of Sciences of the United States of America},
           month = {December},
            year = {2017},
          number = {50},
        keywords = {Parkinson's disease, {\ensuremath{\alpha}}-synuclein, SUMOylatio, nubiquitination, aggregation},
          author = {Rott, R and Szargel, R and Shani, V and Hamza, H and Savyon, M and Abd Elghani, F and Bandopadhyay, R and Engelender, S},
             url = {https://doi.org/10.1073/pnas.1704351114},
        abstract = {{\ensuremath{\alpha}}-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated {\ensuremath{\alpha}}-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates {\ensuremath{\alpha}}-synuclein degradation. We report that PIAS2 promotes SUMOylation of {\ensuremath{\alpha}}-synuclein, leading to a decrease in {\ensuremath{\alpha}}-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in {\ensuremath{\alpha}}-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases {\ensuremath{\alpha}}-synuclein levels by relieving the inhibition exerted on {\ensuremath{\alpha}}-synuclein proteasomal degradation. {\ensuremath{\alpha}}-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated {\ensuremath{\alpha}}-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of {\ensuremath{\alpha}}-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of {\ensuremath{\alpha}}-synuclein by PIAS2 promotes {\ensuremath{\alpha}}-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on {\ensuremath{\alpha}}-synuclein. Second, SUMOylation facilitates {\ensuremath{\alpha}}-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of {\ensuremath{\alpha}}-synuclein SUMOylation provide a strategy to reduce {\ensuremath{\alpha}}-synuclein levels and possibly aggregation in PD.},
            issn = {0027-8424}
}