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

Toshiya Oba,Taro Saito,Akiko Asada,Sawako Shimizu,Koichi M Iijima,Kanae Ando

doi:10.1074/jbc.ra120.014420

Abstract

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 de novo 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 MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356-dependent and -independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo Together, these findings suggest that MARK4ΔG316E317D 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.

Highlights

Accumulation of the microtubule-associated protein tau is a pathological hallmark of Alzheimer’s disease (AD) and other neurodegenerative diseases [1,2,3,4,5,6]
Accumulating evidence suggests that Par-1/microtubule affinity– regulating kinase (MARK) plays an initiating role in tau abnormalities leading to disease pathogenesis [11,12,13,14, 16,17,18]
We previously reported that Par-1 overexpression increases, and knockdown decreases, tau phosphorylation at Ser-262 and Ser-356, which leads to accumulation of tau and exacerbation of neurodegeneration in a fly model of tau toxicity [11, 12]

Summary

Introduction

Accumulation of the microtubule-associated protein tau is a pathological hallmark of AD and other neurodegenerative diseases [1,2,3,4,5,6]. Both MARK4wt and MARK4DG316E317D increased the levels of total tau and tau phosphorylated at Ser-262 and Ser-356; MARK4DG316E317D had stronger effects on both (Fig. 1B). MARK4wt or MARK4DG316E317D had similar kinase activities (Fig. 3), indicating that the higher level of tau accumulation in cells expressing MARK4DG316E317D was not due to a difference in kinase activity.

Results

Conclusion