Dissecting the role of Tau-induced changes of SUMO and succinylCoA conjugation in mitochondrial-nuclear anterograde and retrograde signaling in FTD - Summary Protein aggregation and deposition in the brain is a striking feature of several neurodegenerative disorders including frontotemporal dementia (FTD), which accounts for up to 15% of dementias. There are currently no disease-modifying treatments for FTD, due, in part, to the lack of disease models that accurately recapitulate the complex pathology of the disease. FTD-Tau accounts for 30–50% of FTD cases and is pathologically identified by the presence of insoluble Tau aggregates, which are more prone to appear in the presence of Tau mutations. Mitochondrial function is disrupted in diseases attributed to aggregate-prone proteins, and this disruption might activate a crosstalk with the nucleus and cytoplasm through signaling pathways including several transcriptional, translational and post-translational programs (mitochondrial stress response). This project seeks to address the role played by succinylation and SUMOylation, two post-translational modifications (PTMs), in the mitochondrial-nuclear communication mediated Tau toxicity, in the context of FTD. SUMOylation consists in the covalent and reversible attachment of an 11 kDa SUMO (Small Ubiquitin-like MOdifier) to a target protein. There are three known SUMO paralogs in vertebrate brains, SUMO1-3, which are primarily localized in the nucleus but can also be found in the cytoplasm and associated with mitochondrial proteins. SUMO2, the most expressed, has been found to be neuroprotective in conditions of cellular stress. Succinylation is mediated by metabolic intermediates generated within the mitochondrial tricarboxylic acid (TCA) and has been linked to neurodegeneration. Intriguingly, Tau can be SUMOylated and succinylated, under certain conditions, but little is known about the effects of these PTMs. We found that i) mitochondrial respiratory chain (RC) enzymes, particularly succinate dehydrogenase (SDH, which converts succinate to fumarate in the TCA cycle), are impaired in brain extracts of the PS19 mice, which express P301S Tau; ii) SUMO2 is displaced from the nucleus of PS19 neurons; iii) succinylation is increased and SUMO2 levels and conjugation are reduced in FTD patients iPSC-derived neurons and in PS19 mice; iv) overexpression of SUMO2 rescues RC defects and reduces the aggregation of mutant Tau (mTau) in PS19 mice; v) several mitochondrial pathways are altered in excitatory neurons of PS19 mice. Thus, we hypothesize that in FTD, 1) dysregulation of succinylation plays a role in mTau- induced toxicity; 2) mTau toxicity is counteracted by SUMO2; 3) hypersuccinylation occurs at the detriment of neuroprotective SUMO2ylation, further aggravating Tau toxicity. By using patients’ iPSCs-derived neurons expressing mTau, their isogenic controls, and PS19 mice, we will investigate 1) the causal relationship between Tau-induced mitochondrial dysfunction and alterations of retrograde mito-nuclear signaling through succinylation, 2) whether aberrant crosstalk between succinylation and SUMOylation drives Tau aggregation and toxicity, 3) Tau-induced cell-specific transcriptional programs mediated by altered succinylation and SUMO2ylation, and whether SUMO2 counteracts mitochondrial dysfunction by relocating to mitochondria.
