Summary Our poor understanding of the molecular mechanisms that underlie the cognitive and behavioral impairments that characterize FTD stands as a critical barrier to identifying effective treatments. This project will seek to address this gap in knowledge by examining how SUMOylation, a post-translational modification that our labs found to be impaired in FTD models, controls Tau aggregation and pathological action of Tau on mitochondrial and synaptic functions in animal models as well as patient-derived neurons associated with Tau mutations. SUMOylation, the covalent and reversible attachment of an 11 kDa SUMO (Small Ubiquitin-like MOdifier) protein to target proteins, has been implicated in both Tau aggregation and mitochondrial dynamics. There are three known SUMO paralogs in vertebrate brains, SUMO1-3, with SUMO2 and 3 sharing ~95% sequence homology (and not functionally differentiated) often collectively referred to as SUMO2/3. While SUMO1 conjugation to Tau was previously reported to promote its aggregation and mislocalization, we found that SUMO2 conjugation reduces Tau aggregation and restores its normal distribution in neurons. Moreover, we found that animal models of FTD, expressing the Tau mutations P301S (PS19 mice) show: 1) deficits in mitochondrial respiratory chain enzymes (RCE) activities, as well as impaired synaptic function (LTP); and 2) increased SUMO1- and reduced SUMO2- conjugation. Most importantly, overexpression of SUMO2 improved RCE activities in vitro, as well as LTP and memory in vivo. Furthermore, treating mice with a bioavailable polypeptide that promotes SUMO2 conjugation (BioSenA), rescued LTP and memory loss in FTD mice. Based on these preliminary results, we hypothesize that aggregated and mislocalized Tau causes mitochondrial dysfunction, which results in aberrant SUMOylation and synaptic deficits; and that increasing SUMO2 conjugation rescues oTau-induced defects in mitochondria, and synaptic function and memory, by preventing Tau aggregation. We will test our hypotheses with the following three specific aims: 1. Determine the causal relationship between SUMO conjugation and Tau-induced mitochondrial dysfunction; 2. Test whether overexpression of SUMO1 has a detrimental effect on mitochondrial/synaptic function; 3. Test whether overexpression of SUMO2 rescues the mitochondrial/synaptic axis dysfunction in FTD models. These aims will be addressed through a combination of electrophysiological, behavioral, biophysical, and biochemical techniques in wild-type and genetically modified mice as well as iPSC-derived neurons from FTD patients. Upon the completion of these experiments, we will identify the mechanisms whereby SUMOylation controls the development of tau-related impairments in FTD, and test the possibility that interventions that target SUMO2 conjugation could constitute an effective therapeutic approach for their treatment.