Microtubule Affinity-Regulating Kinase family members differently affect tau phosphorylation and toxicity in a Drosophila model

Accumulation of abnormally phosphorylated tau is thought to cause neuronal loss in Alzheimer's disease (AD) and related neurodegenerative disorders. Tau phosphorylation at Ser262 and Ser356 in the KXGS motifs of microtubule-binding repeats plays a critical role in its physiological function and AD pathogenesis. Members of the Microtubule Affinity-Regulating Kinase family (MARK1-4) phosphorylate these residues and are considered potential therapeutic targets for AD. However, whether and how each member affects tau toxicity in vivo is unclear. By using a Drosophila model of tau toxicity, we compared the effect on tau-induced neurodegeneration among MARKs. We found that MARK4, but not other MARKs, promotes tau accumulation. All MARKs increased tau phosphorylation at Ser262, and MARK1, MARK2, and MARK4 increased tau phosphorylation at Ser356. The levels of AT8-tau were decreased with co-expression of MARK2 and MARK3 but not with MARK1 and MARK4, and tau phosphorylation at Ser396 was elevated only with MARK4. MARK4 enhanced tau-induced neurodegeneration more than other MARKs. Our results suggest that MARK4 promotes tau accumulation via enhancing additional phosphorylation and that inhibition of MARK4 may be an effective treatment for AD and related tauopathies.