A Phenotype-Optimized Zebrafish Model of Progressive Supranuclear Palsy

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Abstract Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized clinically both by profound loss of balance and other neurological symptoms. Falls are central to early PSP presentation and diagnosis and lead to fractures and hospitalization. No current treatments improve balance or prevent disease progression. Strong pathological, molecular, and genetic evidence implicates deposits of the 4­repeat isoform of the micro­ tubule associated protein Tau (4R­Tau) in PSP pathophysiology. Current models struggle to link 4R­Tau pathol­ ogy to the debilitating falls that define PSP. Development of new therapies for PSP would benefit profoundly from a means to evaluate interventions in the context of the neural circuits responsible for balance. Leveraging the historical strengths of our individual laboratories, we have worked together to design a new model system to model Tau pathology in the context of balance. Our model system uses the larval zebrafish, a small vertebrate with exceptional molecular and optical accessibility and rigorously defined balance behavior. In unpublished pilot experiments have used a wide set of neurological and behavioral tests show that express­ ing 4R­Tau in zebrafish neurons gives rise to: (i) molecular and cellular pathology (ii) locomotor and oculomotor deficits (iii) systematic balance deficits that together resemble PSP. Here we propose to extend and validate this new and exciting model. In the R61 aim, to validate our model internally we will develop two complementary pipelines to assay balance behavior and establish new transgenic lines and protocols to gain temporal control of 4R­Tau expression. First, we will optimize an assay of balance with rigorously­defined quantitative behavioral endpoints suitable for effi­ cient evaluation of chemical modifiers or candidate gene targets. Next we will use a novel light­inducible trans­ gene expression system (GAVPO/UAS) for parametric control of 4R­Tau levels at particular time points. If our balance assay and transgenic lines meet defined milestones for success, we will proceed to the R33 aim. There, we will validate our model externally along three axis: First, we will assay construct validity by testing if a hu­ man pathogenic Tau mutant enhances the severity of observed phenotypes. Second we will assay face validity by evaluating the pathology, neurological and balance deficits following induction of 4R­Tau. Lastly we will as­ say predictive validity by administering chemicals known to modulate tauopathy in other model systems. Our team consists of a physician scientist specializing in movement disorders (in the clinic) and zebrafish models of neurodegeneration (in the lab) and a basic neuroscientist who has successfully used zebrafish to understand normal development and function of neural circuits responsible for balance. Together, we propose to establish and validate an innovative new “phenotype­optimized” model system to address a deep unmet clinical need: neurotherapeutic discovery for PSP in the context of its definitive balance symptoms. The work is broadly signif­ icant as it advances our ability to define general mechanisms of neurodegeneration.