Suppression of Tau Phosphorylation Induces Neurotoxicity, Causing Developmental Defects and Degeneration in C....

Tau hyperphosphorylation is a hallmark of tauopathies and is closely associated with neurodegeneration. While targeting kinases and phosphatases to suppress tau phosphorylation has become an increasingly attractive therapeutic approach, the functional significance of tau phosphorylation and the potential risks of suppressing this process are not fully understood. Using C. elegans, we introduced non-phosphorylatable tau mutations (hTauAP) to model the suppression of tau phosphorylation. Unexpectedly, we found that hTauAP induced severe neurotoxicity, resulting in behavioural deficits and severe neurite abnormalities. This neurotoxicity is associated with excessive accumulation of hTauAP on microtubules, leading to both neurite developmental defects and adult neurite degeneration. The neurotoxic effects of hTauAP require its microtubule-binding domain (MTB) and are primarily driven by the loss of phosphorylation in the C-terminal region (CTR). Removing either domain reduces microtubule association and suppresses toxicity. Within CTR, suppressing phosphorylation at S396 or S404 is critical for neurotoxicity. These findings highlight the essential role of tau phosphorylation in neuronal function and underscore the potential risks of broadly suppressing tau phosphorylation as a therapeutic strategy.