SUMOylation is a covalent and reversible attachment of an 11 kDa SUMO (Small Ubiquitin-like MOdifier) protein to a lysine residue. SUMOylation act as a biochemical switch to regulate the function of hundreds of proteins in different pathways. In the brain of vertebrates, three main SUMO isoforms (SUMO1-3) are characterized. While SUMO2 and SUMO3 differ by only three N-terminal amino acids, they only share ~50% of their sequences with SUMO1. Global levels of SUMOylated proteins are altered in several neurodegenerative diseases; however, no data are currently available in Fronto-temporal dementia (FTD), the second most common form of dementia. Here we measured SUMOylation in animal models of FTD, as well as in iPSC-derived neurons from patients. In brain extracts from PS19 and JNPL3 mice, which express P301S and P301L Tau mutation associated with FTD, we found increased levels of SUMO1 and decreased levels of SUMO2 conjugated proteins. Similar changes were found in iPSC-derived neurons with R406W and P301L mutation. Since increase in SUMO2 conjugation has been previously reported to be neuroprotective, to test whether enhanced SUMO2ylation could ameliorate some aspects of mutant Tau-induced alterations, we treated iPSC-derived neurons with molecules that inhibit SUMO deconjugation. We found that increase of SUMO2 conjugation was accompanied by a recovery in the levels of synaptic proteins and a reduction of Tau pathology.Our results uncover an endogenous neuroprotective mechanism in FTD patients-derived cells, whereby SUMO2 conjugation reduces Tau-induced synaptic dysfunctions. These findings bring to light the potential therapeutic implication of manipulating SUMO conjugation in Tauopathies.