MUSASHI1 promotes tau phosphorylation by activating the p38 MAPK pathway

Aberrant phosphorylation of the Tau protein represents a critical event in the pathogenesis of Alzheimer's disease (AD); however, therapeutic interventions specifically targeting this modification remain limited. Therefore, a thorough understanding of the molecular mechanisms underlying Tau hyperphosphorylation is essential for the development of effective preventive and therapeutic strategies against AD. The RNA-binding protein MUSASHI1 (MSI1) is recognized for its significant role in neurodevelopment, and previous studies have reported its dysregulated overexpression in the brains of AD patients. In the current investigation, we demonstrate that MSI1 expression progressively increases in parallel with the advancement of Tau pathology in P301S transgenic mouse models. Furthermore, our findings suggest that MSI1 activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway, thereby promoting Tau phosphorylation. Additionally, we have identified two microtubule-associated proteins as novel potential interaction partners of MSI1 within neuronal cells. Collectively, these results reveal a previously uncharacterized mechanism that may contribute to aberrant Tau phosphorylation in AD, offering new directions for future research in this field.