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A commentary on Analysis of SUMO1-conjugation at synapses by Daniel, J. A., Cooper, B. H., Palvimo, J. J., Zhang, F. P., Brose, N., and Tirard, M. (2017). eLife 6:e26338. doi: 10.7554/eLife.26338 There is a large and growing literature on protein SUMOylation in neurons and other cell types. While there is a consensus that most protein SUMOylation occurs within the nucleus, SUMOylation of many classes of extranuclear proteins has been identified and, importantly, functionally validated. Notably, in neurons these include neurotransmitter receptors, transporters, sodium and potassium channels, mitochondrial proteins, and numerous key pre- and post-synaptic proteins (for reviews see Martin et al., 2007b; Scheschonka et al., 2007; Craig and Henley, 2012; Luo et al., 2013; Guo and Henley, 2014; Henley et al., 2014; Wasik and Filipek, 2014; Peng et al., 2016; Schorova and Martin, 2016; Wu et al., 2016). Furthermore, several groups have reported SUMO1-ylated proteins in synaptic fractions using biochemical subcellular fractionation approaches, using a range of different validated anti-SUMO1 antibodies (Martin et al., 2007a; Feligioni et al., 2009; Loriol et al., 2012; Luo et al., 2013; Marcelli et al., 2017) and many studies have independently observed colocalization of SUMO1 immunoreactivity with synaptic markers (Martin et al., 2007a; Konopacki et al., 2011; Gwizdek et al., 2013; Jaafari et al., 2013; Hasegawa et al., 2014; Ghosh et al., 2016). Tirard and co-workers (Daniel et al., 2017) directly challenge this wealth of compelling evidence. Primarily using a His6-HA-SUMO1 knock-in (KI) mouse, the authors contest any significant involvement of post-translational modification by SUMO1 in the function of synaptic proteins.