MARK4 enhances stress granule formation under oxidative stress and increases tau accumulation

Overactivation of Microtubule affinity regulating kinase 4 (MARK4) is believed to contribute to Alzheimer's disease pathogenesis. MARK4 promotes the accumulation of the microtubule-binding protein tau, thereby enhancing tau-induced neurodegeneration. However, the underlying mechanisms by which MARK4 enhances tau accumulation are not fully understood. T-cell intracellular antigen 1 (TIA1), a critical regulator of stress granule (SG) formation, has been suggested to initiate tau abnormality. Here, we report that MARK4 and TIA1 synergistically induce stress granule (SG) formation. MARK4 is localized in SGs with TIA1 in mammalian cultured cells and primary neurons. MARK4 suppresses TIA1 dimerization and enhances SG formation under oxidative stress. Co-expression of MARK4 and TIA1 promotes tau accumulation, and knockdown of a fly ortholog of TIA1 suppressed tau toxicity in a Drosophila model. These results identify MARK4 as a novel regulator of SG formation and suggest a mechanistic link between oxidative stress and tau pathology.