Progressive supranuclear palsy (PSP) is associated with prominent motor, oculomotor, bulbar and cognitive abnormalities.  There are no effective treatments and prognosis is poor.  Pathology is characterized by neuronal loss and accumulation of abnormal aggregates of the 4-repeat isoform of the microtubule-associated protein Tau (4R-Tau) in CNS neurons.  Genetic evidence suggests that 4R-Tau is central to pathogenesis.

The long-term objective of our work is to develop effective treatments for progressive supranuclear palsy (PSP).  The objective of the present study was to identify small molecules that rescue 4R-tauopathy phenotypes in vivo, by screening chemical libraries against a novel zebrafish model of PSP.

We developed a novel transgenic zebrafish model expressing human 4R-Tau in the CNS.  Using endpoint assays that quantify phenotypes relevant to PSP, and provide sufficient throughput and suitable metrics for discovery screening, we evaluated two different chemical libraries against this model to isolate small molecules that ameliorate the Tau-dependent neurological phenotypes.

Transgenic zebrafish expressing human 4R-Tau showed: impaired survival; a hypokinetic motor disorder suitable for high-throughput screening using automated methods; oculomotor abnormalities; and histopathological changes including tauopathy and microgliosis. Our screens identified several chemicals that rescued motor function and passed subsequent verification tests for specificity.  Some of the compounds also rescued oculomotor function and histopathological changes, suggesting bona fide anti-tauopathy actions in vivo. 

We have developed a novel drug discovery platform for PSP and related tauopathies, and validated our approach by isolating chemical modifiers that rescue neurological function.  Since the novel mechanisms of action include cell non-autonomous effects and rescue of synaptic function, these chemicals would not have been identified using cultured cells or biochemical assays.  Our unbiased approach using disease-relevant endpoints in vivo will open new avenues for drug discovery in tauopathy and other neurodegenerative diseases.