Citrullinated Tau as a Therapeutic Target in Tauopathies

Technical Abstract The number of tauopathies including Alzheimer’s disease (AD) continues to increase and impact neuronal health. Despite worldwide efforts, no disease modifying agents exist in the clinic for tauopathies. Tau deposition elicits different clinical phenotypes and pathological outcomes depending on the tau strain and region of the brain. The pathological sequalae likely stems from post-translational modifications (PTMs) that alter structure, function and regional susceptibility. Our group recently uncovered a novel PTM of tau, named citrullination, caused by the enzyme peptidylarginine deiminase (PADs). PAD- induce citrullination irreversibly converts arginine residues within proteins/ peptides to citrulline. Structurally, this conversion permanently alters the target by producing loss of positive charges, changes in protein stability, inter/ intramolecular interactions, and increased hydrophobicity. We uncovered several findings indicating that: 1) tau can become citrullinated at all 14 arginine residues; 2) tau citrullination prevents fibrillization but increases oligomers; 3) novel citR-tau antibodies show various tau deposition profiles in mice with tauopathies; 4) AD brains and other tauopathies show increased citR tau; 5) certain citR tau epitopes impact neighboring phosphorylation sites; and 6) citR tau is cleared slower by the 20s proteosome. Our data indicate that citrullination impacts multiple functional domains that influence tau fate. We posit that PAD4- induced citR tau promotes synaptic toxicity, inflammation, neurodegeneration, and cognitive impairment. We will test the hypothesis that pharmacological inhibitors of PAD and/ or immunotherapy to key citR tau sites will mitigate the effects. Aim1 will functionally determine how PAD4 inhibitors impact transcriptomic signatures and neuropathological changes following aberrant tau citrullination. Aim2 will functionally determine if immunotherapy against a specific citR tau epitope (citR349) targeting the filament core is sufficient to curtain general tau pathology, improve synaptic function and neuropathological changes compared to PAD inhibitor and global citrullination. As a final and future goal, we wish to discriminate differences between PAD inhibitors vs. immunotherapy and how they impact clinical aggressiveness and cognitive decline without affecting a host of other bodily systems.