Microtubule affinity-regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration.

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity-regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4 increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356-dependent and -independent mechanisms. Using transgenic expressing human MARK4 (MARK4) or a mutant version of MARK4 (MARK4), we found that coexpression of MARK4 and MARK4 increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4 had more potent effects than MARK4 Interestingly, the kinase activities of MARK4 and MARK4 were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4 did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4 did. Both MARK4 and MARK4 increased the levels of oligomeric forms of tau; however, only MARK4 further increased the detergent insolubility of tau Together, these findings suggest that MARK4 increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.