Linking molecular abnormalities to balance deficits using a zebrafish model for tauopathies

Abstract Background The ability to maintain balance is an evolutionarily‐conserved behavior that is frequently disrupted found in patients with neurodegenerative diseases. One of the most prominent balance disorders is found in patients with progressive supranuclear palsy (PSP), a primary tauopathy pathologically characterized by tau over‐representation in the brainstem vestibulospinal (VS) nucleus, where they frequently exhibit accidental‐backward falls starting from the early stage of the disease. Although pathological features of PSP correlate well with its clinical phenotype, how tau aggregation affects neuronal and circuit functions, which eventually leads to behavioral deficits, remains unclear. Method To dissect disease mechanisms across molecular, cellular, circuitry, and behavioral levels, we generated tau fish by expressing human 0N/4R‐Tau in zebrafish VS nucleus. Tau expression and phosphorylation were validated using immunohistochemistry staining with PHF‐1 antibody. To examine the effect of tau on balance behavior, we measured postural control of free‐swimming tau fish and compared to that of tau‐negative siblings. Moreover, we tested response of VS neurons to nose‐down and nose‐up tilt stimulus using 2‐photon calcium imaging. Result Ttau‐expressing zebrafish exhibit impaired balance control while maintaining normal locomotor ability. Interestingly, we did not observe any neuronal death in the VS nucleus. Functional imaging of the VS nucleus shows impaired directional tuning in tau‐expressing neurons in response to tilt stimulus. We also found ectopic accumulation of acidic organelles in the cell bodies of tau‐positive neurons, suggesting abnormal lysosomal function. Conclusion Our results demonstrate how molecular abnormalities disrupt specific behavior in tauopathies before neurodegeneration appeared.