Project Grant RF1AG072703

VALIDATION OF A NOVEL TAU CLEARANCE MECHANISM. - BESIDES EXTRACELLULAR SS-AMYLOID (ASS) PLAQUES DEPOSITION, ALZHEIMER'S DISEASE (AD) IS PATHOLOGICALLY CHARACTERIZED BY INTRACELLULAR TAUOPATHY THAT ACCUMULATION AND AGGREGATION OF ABNORMALLY HYPERPHOSPHORYLATED MICROTUBULE-ASSOCIATED PROTEIN MAPT/TAU FORM NEUROFIBRILLARY TANGLE (NFT), RESULTING IN LOSS OF FUNCTIONAL NEURONS. ALTHOUGH ASS PLAQUES PLAY A KEY ROLE IN INITIATING AD PATHOGENESIS, THE SEVERITY OF COGNITIVE DECLINE CORRELATES BEST WITH THE BURDEN OF NEOCORTICAL NFTS. THEREFORE, PROMOTING THE CLEARANCE OF ACCUMULATED TAU REPRESENTS A PROMISING THERAPEUTIC STRATEGY FOR TAUOPATHY PATIENTS, WHICH DEPENDS ON A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE DEGRADATION OF PATHOLOGICAL TAU SPECIES DURING DISEASE PROGRESSION. OUR ULTIMATE GOAL IS TO ELUCIDATE THE COMPLEX MECHANISMS UNDERLYING HOW TAUOPATHIES, SUCH AS AD, INITIATE AND PROGRESS, AND TO DEVELOP EFFECTIVE THERAPEUTIC APPROACHES TO TREAT TAUOPATHIES. IT IS REPORTED THAT TAU CAN BE DEGRADED BY AUTOPHAGY-LYSOSOMAL OR UBIQUITIN-PROTEASOMAL SYSTEMS. TAU DEGRADATION IS CLOSELY ASSOCIATED WITH ITS VARIOUS POST-TRANSLATIONAL MODIFICATIONS, INCLUDING PHOSPHORYLATION, ACETYLATION, AND UBIQUITINATION. OUR PRELIMINARY STUDIES INDICATE THAT TAU IS MODIFIED BY LINEAR UBIQUITIN CHAINS IN NORMAL MOUSE BRAIN TISSUES, WHICH WERE SUBSTANTIALLY DECREASED IN TAUOPATHY MOUSE MODELS. LINEAR UBIQUITINATION OF TAU PROMOTES TAU CLEARANCE IN AN AUTOPHAGY-DEPENDENT MANNER. WE FURTHER FOUND THAT OXIDATIVE STRESS CAN INCREASE DEUBIQUITINASE OTULIN ACTIVITY BY PROMOTING ITS PHOSPHORYLATION, WHICH BOTH ARE SUBSTANTIALLY INCREASED IN THE BRAIN TISSUES FROM AD PATIENTS. INHIBITION OF OTULIN PREVENTED THE ACCUMULATION OF PATHOLOGICAL TAU SPECIES AND ATTENUATED ITS CYTOTOXICITY IN A TAUOPATHY MOUSE MODEL. THEREFORE, WE HYPOTHESIZE THAT LINEAR UBIQUITINATION PROMOTES TAU DEGRADATION, WHICH IS INHIBITED BY DEUBIQUITINASE OTULIN; OXIDATIVE STRESS ACTIVATES OTULIN, RESULTING IN INCREASED TAU AGGREGATION AND NEUROTOXICITY. PHARMACOLOGICAL INHIBITION OF OTULIN MAY MITIGATE TAUOPATHY PROGRESSION BY ENHANCING THE CLEARANCE OF TAU AGGREGATES. THREE SPECIFIC AIMS ARE PROPOSED TO TEST THIS HYPOTHESIS. AIM1 WILL DETERMINE THE ROLE OF LINEAR UBIQUITINATION IN REGULATING TAU ACCUMULATION AND NEURONAL TOXICITY AND INVESTIGATE THE AUTOPHAGIC-LYSOSOMAL MECHANISM. AIM2 WILL INVESTIGATE OXIDATIVE STRESS-MEDIATED MECHANISMS DURING OTULIN-INDUCED TAUOPATHIES USING A SYSTEMS BIOLOGY APPROACH. AIM 3 WILL TEST A NEWLY DEVELOPED OTULIN INHIBITOR IN PROMOTING TAU CLEARANCE AND MITIGATING ITS CELLULAR TOXICITY IN TAUOPATHY ANIMAL MODELS. OUR STUDIES WILL HAVE A STRONG IMPACT BY PROVIDING: 1) NOVEL MECHANISMS REGULATING TAU AGGREGATION AND PROTEOTOXICITY; 2) NEW MECHANISTIC LINK BETWEEN OXIDATIVE STRESS AND TAU LINEAR UBIQUITINATION; 3) POTENTIAL THERAPEUTIC APPROACHES FOR MITIGATING TAUOPATHY AND COGNITIVE DECLINE, EVENTUALLY BENEFITING AD PATIENTS.