Project Grant R01AG084552

INVESTIGATING HOW SUT-6/NIPP1 REGULATES PATHOLOGICAL TAU - BACKGROUND: ALZHEIMER'S DISEASE AND OTHER NEURODEGENERATIVE DISEASES WITH ACCUMULATION OF PATHOLOGICAL TAU PROTEIN, TERMED TAUOPATHIES, ARE INCREASING IN PREVALENCE AND BURDEN TO THE US POPULATION. HOWEVER, THERE ARE STILL NO THERAPIES TO CURE OR REVERSE TAUOPATHIES. DESPITE STRONG EVIDENCE THAT PATHOLOGICAL TAU CAUSES NEURODEGENERATION AND THE DEVELOPMENT OF NUMEROUS MODELS OF TAU TOXICITY, THE MOLECULAR MECHANISMS UNDERLYING THE TOXICITY INDUCED BY PATHOLOGICAL TAU ARE STILL INCOMPLETELY UNDERSTOOD. TO DISCOVER NOVEL GENETIC SUPPRESSORS OF TAU TOXICITY, FORWARD GENETIC SCREENING WAS PERFORMED IN A CAENORHABDITIS ELEGANS MODEL OF TAUOPATHY. A W292X MUTATION IN SUT-6 (NIPP1 IN MAMMALS) WAS RECENTLY IDENTIFIED AS A NOVEL MODULATOR OF TAUOPATHY. SUT-6/NIPP1 IS A MULTIFUNCTIONAL, MULTIDOMAIN PROTEIN THAT REGULATES PHOSPHATASE ACTIVITY, SPLICING OF MRNAS, AND GENE TRANSCRIPTION. THE W292X MUTANT OF SUT-6 REMOVES THE LAST 11 AMINO ACIDS OFF THE C- TERMINUS OF SUT-6 AND SHOWS STRONG, DOMINANT AND CELL-AUTONOMOUS SUPPRESSION OF TAU-INDUCED TOXICITY WHILE LOSS OF SUT-6 EXPRESSION SHOWS WEAKER SUPPRESSION OF TAU-INDUCED TOXICITY. THIS SUGGESTS THAT ALTERING SUT- 6/NIPP1 INTERACTIONS WITH PROTEIN PARTNERS THAT REGULATE PHOSPHATASE, SPLICING, OR OTHER ACTIVITIES LEADS TO SUPPRESSION OF TAU TOXICITY. HYPOTHESIS: SUT-6/NIPP1 MODULATES TAU TOXICITY BY ALTERING PROTEIN PHOSPHATASE 1 AND/OR SPLICING ACTIVITY IN TRANSLATIONALLY CONSERVED MECHANISMS OF DISEASE. PROPOSAL AIMS: THE SPECIFIC AIMS OF THIS PROJECT ARE: 1) DEFINE THE FUNCTIONS OF SUT-6/NIPP1 IMPORTANT FOR SUPPRESSING TAU TOXICITY BY INTRODUCING MUTATIONS INTO THE SUT-6 GENE AND EVALUATING THE EFFECTS IN A C. ELEGANS MODEL OF TAU PATHOLOGY. 2) DETERMINE DOWNSTREAM MEDIATORS OF SUT-6/NIPP1'S SUPPRESSION OF TAU TOXICITY BY IDENTIFYING NEURONAL INTERACTORS OF SUT-6 AND NIPP1 AND PERFORMING EPISTASIS ANALYSIS OF IDENTIFIED INTERACTORS IN A C. ELEGANS MODEL OF TAU PATHOLOGY. 3) EXAMINE THE TRANSLATIONAL IMPACT OF NIPP1 MODULATION ON TAUOPATHY USING A MOUSE MODEL OF TAU PATHOLOGY. EXPECTED OUTCOMES: THE PROPOSED STUDIES WILL DEEPEN OUR UNDERSTANDING OF A NOVEL, TRANSLATIONALLY RELEVANT MECHANISM FOR REGULATING TAUOPATHY AND OUR OVERALL KNOWLEDGE OF THE MECHANISMS OF TAU-INDUCED TOXICITY, PATHOLOGY AND DISEASE GENERALLY. THIS KNOWLEDGE WILL LEAD TO BETTER THERAPEUTIC STRATEGIES TARGETING TAU IN ALZHEIMER'S DISEASE AND OTHER TAUOPATHIES.