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

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. 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. Accumulation of the microtubule-associated protein tau is a pathological hallmark of AD and other neurodegenerative diseases (1Wang Y. Mandelkow E. Tau in physiology and pathology.Nat. Rev. Neurosci. 2016; 17 (26631930): 5-2110.1038/nrn.2015.1Crossref PubMed Scopus (224) Google Scholar, 2Grundke-Iqbal I. Iqbal K. Tung Y.C. Quinlan M. Wisniewski H.M. Binder L.I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.Proc. Natl. Acad. Sci. U. S. A. 1986; 83 (3088567): 4913-491710.1073/pnas.83.13.4913Crossref PubMed Google Scholar, 3Hasegawa M. Morishima-Kawashima M. Takio K. Suzuki M. Titani K. Ihara Y. Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain.J. Biol. Chem. 1992; 267 (1512244): 17047-17054Abstract Full Text PDF PubMed Google Scholar, 4Hanger D.P. Betts J.C. Loviny T.L. Blackstock W.P. Anderton B.H. 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In this we a Drosophila to the effects of MARK4 the mutation on tau accumulation and toxicity with those of MARK4 that coexpression of MARK4ΔG316E317D increases the abundance of highly phosphorylated and insoluble tau in enhanced accumulation and toxicity of via a novel gain-of-function the the effects of MARK4wt and MARK4ΔG316E317D on and toxicity of tau in we transgenic human MARK4wt or MARK4ΔG316E317D the of a sequence sequence MARK4wt or MARK4ΔG316E317D was with human tau in the using the that these MARK4wt and MARK4ΔG316E317D at levels MARK4 phosphorylates tau at Ser-262 and Ser-356 B. M. A. MARK4 is a novel microtubule-associated kinase that to the microtubule and to Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and we that tau phosphorylation at Ser-262 and Ser-356 by a of the tau and increases total tau levels K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar, K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google Scholar). Both MARK4wt and MARK4ΔG316E317D increased the levels of total tau and tau phosphorylated at Ser-262 and MARK4ΔG316E317D had effects on Ser-262 tau and tau not tau species that are not phosphorylated at sites K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar, K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google and in tau phosphorylated at Ser-356 by MARK4ΔG316E317D is tau phosphorylation at Ser-356 in this abnormally elevated K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google Scholar). of MARK4wt or MARK4ΔG316E317D did not affect the levels of tau that the in tau levels was not to elevated of the tau we the of coexpression of MARK4 on tau toxicity. of human tau in the and neurodegeneration in the the of the K. Sekiya M. Maruko-Otake A. Ohtake Y. Suzuki E. Lu B. Iijima K.M. of neurodegeneration and Alzheimer's tau phosphorylation via Genet. 2012; 8 PubMed Scopus Google Scholar). found that tau and MARK4wt or MARK4ΔG316E317D more neurodegeneration in the than those expressing tau coexpression of MARK4ΔG316E317D more neurodegeneration than the coexpression of MARK4wt A and of MARK4wt or MARK4ΔG316E317D did not cause neurodegeneration at the A and Together, these suggest that MARK4ΔG316E317D tau accumulation and exacerbates tau toxicity to a than MARK4wt. A were with tau and MARK4wt or with MARK4ΔG316E317D a in tau Ser-262 phosphorylation to those with MARK4wt A. C. D. C. K. S. S. novo a on Aβ in Alzheimer PubMed Google Scholar). was that the de novo mutation in MARK4 increases the of MARK4 to phosphorylate tau on Ser-262 more A. C. D. C. K. S. S. novo a on Aβ in Alzheimer PubMed Google Scholar). However, it not MARK4ΔG316E317D kinase than MARK4wt. this we an in vitro kinase we MARK4wt or MARK4ΔG316E317D in MARK4 proteins from and kinase activities using tau a MARK4wt or MARK4ΔG316E317D had kinase activities that the of tau accumulation in expressing MARK4ΔG316E317D was not to a in kinase that tau accumulation via its phosphorylation at Ser-262 and Ser-356 and neurodegeneration K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar, K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google Scholar). the of tau accumulation and toxicity by MARK4wt or MARK4ΔG316E317D is by tau phosphorylation at Ser-262 and we a tau mutant in of those sites are by K. A. C. Iijima K. A kinase phosphorylates tau and tau-induced Mol. Genet. 2010; PubMed Scopus Google Scholar). to K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar, K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google the of MARK4wt did not the of tau found that MARK4wt did not exacerbate neurodegeneration by tau suggest that MARK4wt increases tau levels and tau toxicity tau phosphorylation at Ser-262 and Ser-356. MARK4ΔG316E317D increased the levels of tau and coexpression of MARK4ΔG316E317D with tau neurodegeneration suggest that coexpression of MARK4ΔG316E317D increases tau levels and tau toxicity via a novel gain-of-function mechanism that not phosphorylation at Ser-262 and Ser-356. found that MARK4ΔG316E317D increased tau protein levels the levels of tau the the accumulation of tau by we to this is to tau When with MARK4ΔG316E317D did not that the mutant protein not cause accumulation of proteins MARK4ΔG316E317D MARK4 is to the kinase 4 (MARK4) is a of the of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is a conserved of the of a of tau Y. Mandelkow E. of tau protein by and 2012; PubMed Scopus Google Scholar). MARK4wt and MARK4ΔG316E317D had effects on we of MARK4wt or MARK4ΔG316E317D in the found that MARK4wt MARK4ΔG316E317D phosphorylation of a of In MARK4wt MARK4ΔG316E317D or the levels of the and that was not suggest that MARK4ΔG316E317D accumulation of tau via a mechanism other than of protein of tau is with tau S. of tau toxicity and role of and in a Drosophila Mol. Genet. PubMed Scopus Google Scholar, M. S. tau with and in 2002; Full Text Full Text PDF PubMed Scopus Google we MARK4ΔG316E317D increases tau phosphorylation for of the phosphorylation of tau A. K. S. of in phosphorylation of by 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). Drosophila a of the Par-1/MARK we that phosphorylates human tau proteins at Ser-262 and and phosphorylation at other sites I. Y. Lu B. kinase plays an role in a phosphorylation that tau toxicity in Full Text Full Text PDF PubMed Scopus Google Scholar, K. Sekiya M. Maruko-Otake A. Ohtake Y. Suzuki E. Lu B. Iijima K.M. of neurodegeneration and Alzheimer's tau phosphorylation via Genet. 2012; 8 PubMed Scopus Google Scholar). the the effects of MARK4wt and MARK4ΔG316E317D on tau phosphorylation in this we this in a Tau protein in the into that it was phosphorylated in multiple Interestingly, the phosphorylation forms of tau increased on MARK4wt or MARK4ΔG316E317D was MARK4wt increased the of a and coexpression of MARK4ΔG316E317D further increased the of the that MARK4ΔG316E317D increased tau species with phosphorylation in Tau many and sites by are phosphorylated by kinases and kinase K. S. and pathological phosphorylation of tau by Mol. Neurosci. PubMed Scopus Google Scholar, S. A. Iijima K.M. K. increases MARK4 and pathological tau accumulation and toxicity tau phosphorylation at Mol. Genet. PubMed Scopus Google Scholar, A. is in the of Alzheimer's Alzheimer's PubMed Google Scholar, W. Lee Tau in 4 PubMed Google Scholar). not phosphorylate those sites, an in tau levels and increases in tau phosphorylated at sites K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar). MARK4ΔG316E317D accumulation of tau phosphorylated at sites to a than we using tau phosphorylated at the and of tau and MARK4wt increased the levels of tau phosphorylated at these sites and coexpression of tau and MARK4ΔG316E317D further increased them, to of tau sites are not to of MARK4 I. Y. Lu B. kinase plays an role in a phosphorylation that tau toxicity in Full Text Full Text PDF PubMed Scopus Google Scholar, A. U. Mandelkow E.M. Mandelkow E. a novel family of protein kinases that phosphorylate microtubule-associated proteins and microtubule Full Text Full Text PDF PubMed Google and the increases in the tau species are to those in total tau levels that the elevated levels of the tau by coexpression of MARK4wt or MARK4ΔG316E317D are a of the accumulation of total However, we the mutation the and MARK4ΔG316E317D phosphorylates MARK4ΔG316E317D phosphorylates those sites, we an in vitro tau was with MARK4wt or and the phosphorylation of tau was using the Tau the phosphorylation it was with MARK4wt or with MARK4ΔG316E317D that MARK4ΔG316E317D increases accumulation of tau species phosphorylated at sites via an mechanism in vivo. Tau into to and tau phosphorylation at sites this M. S. tau with and in 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Mandelkow E.M. and phosphorylation is critical for tau in Neurosci. 2007; PubMed Scopus Google Scholar). we coexpression of MARK4wt or MARK4ΔG316E317D affect the of and Tau proteins in the Drosophila in the K. A. K. Tau phosphorylation is critical for Aβ42-induced tau toxicity in a transgenic Drosophila of Alzheimer's Mol. Genet. 2010; PubMed Scopus Google Scholar, S. D. M. Drosophila of human that Tau protein toxicity in is by phosphorylated forms of the Neurochem. 2010; PubMed Scopus Google Scholar). found that MARK4wt and MARK4ΔG316E317D increased the levels of and oligomers to to coexpression of MARK4wt or MARK4ΔG316E317D affect the detergent insolubility of we by with S. C. R. Tau aggregation and neuronal in the of in and of Alzheimer's tau in Neurosci. PubMed Scopus Google Scholar). tau proteins in the Drosophila in a K. A. K. Tau phosphorylation is critical for Aβ42-induced tau toxicity in a transgenic Drosophila of Alzheimer's Mol. Genet. 2010; PubMed Scopus Google Scholar, S. D. M. Drosophila of human that Tau protein toxicity in is by phosphorylated forms of the Neurochem. 2010; PubMed Scopus Google When or with MARK4wt or tau was with However, tau proteins were in the tau was with MARK4wt or and this was more MARK4ΔG316E317D was Tau was not in the with MARK4wt or MARK4ΔG316E317D Tau proteins into with the and the of these are related to phosphorylation that tau in the is more phosphorylated at sites than tau in the K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar). Tau species in the were whereas tau proteins in the and with the accumulation of tau species coexpression of not increased the of in the further coexpression with MARK4wt or MARK4ΔG316E317D affects the of In to and forms of were with or coexpression of MARK4wt or MARK4ΔG316E317D oligomers were MARK4wt or MARK4ΔG316E317D did not oligomers suggest that MARK4ΔG316E317D the accumulation of tau other than its these that MARK4wt increases the levels of and MARK4ΔG316E317D the accumulation of not only those tau species insoluble tau may promote neurodegeneration. that Par-1/MARK plays an role in tau to disease K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar, K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google Scholar, I. Y. Lu B. kinase plays an role in a phosphorylation that tau toxicity in Full Text Full Text PDF PubMed Scopus Google Scholar, de M. S. J. I. A. J.C. J. of tau and in a 2016; Full Text Full Text PDF PubMed Google Scholar, J. B. I. Iqbal K. Phosphorylation of tau at and Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, K. Sekiya M. Maruko-Otake A. Ohtake Y. Suzuki E. Lu B. Iijima K.M. of neurodegeneration and Alzheimer's tau phosphorylation via Genet. 2012; 8 PubMed Scopus Google Scholar, K. A. K. Tau phosphorylation is critical for Aβ42-induced tau toxicity in a transgenic Drosophila of Alzheimer's Mol. Genet. 2010; PubMed Scopus Google Scholar). that and tau phosphorylation at Ser-262 and to accumulation of tau and of neurodegeneration in a of tau toxicity K. Maruko-Otake A. Ohtake Y. Hayashishita M. Sekiya M. Iijima K.M. Stabilization of microtubule-unbound tau via tau phosphorylation at Ser-262/356 by Par-1/MARK contributes to augmentation of AD-related phosphorylation and Aβ42-induced tau toxicity.PLoS Genet. 2016; 12 (27023670)e100591710.1371/journal.pgen.1005917Crossref PubMed Scopus (50) Google Scholar, K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google Scholar). In this we found that human MARK4wt increased the levels of and total and increased tau toxicity MARK4wt did not tau levels or affect its toxicity that to affects tau and toxicity tau phosphorylation at Ser-262 and Ser-356. the other we found that MARK4ΔG316E317D tau accumulation via mechanisms. MARK4ΔG316E317D increased tau levels that MARK4ΔG316E317D the abundance of tau that is not phosphorylated at Ser-262 or Ser-356. found that not the accumulation of the forms of tau suggest that MARK4wt accumulation of tau phosphorylated at Ser-262 and Ser-356 and that MARK4ΔG316E317D further increases tau accumulation via mechanisms. MARK4ΔG316E317D accumulation of the of tau that tau in this a MARK4ΔG316E317D is to total tau levels via not only tau other mechanisms. of MARK4ΔG316E317D increased tau levels its that A. C. D. C. K. S. S. novo a on Aβ in Alzheimer PubMed Google that were with tau and MARK4ΔG316E317D with MARK4ΔG316E317D a in tau phosphorylation at Ser-262 to MARK4wt. of that that this de novo mutation in MARK4 in a gain-of-function in the of MARK4 to phosphorylate tau on Ser-262 A. C. D. C. K. S. S. novo a on Aβ in Alzheimer PubMed Google Scholar). found that coexpression of MARK4ΔG316E317D increased the of tau phosphorylated at Ser-262 to a than MARK4wt in However, in vitro kinase that MARK4wt and MARK4ΔG316E317D did not in of kinase the that accumulation of tau is the of more phosphorylation of tau by double mutation is in the linker that the kinase to or A. C. D. C. K. S. S. novo a on Aβ in Alzheimer PubMed Google Scholar). that the double increases the of the a of MARK4 with proteins A. C. D. C. K. S. S. novo a on Aβ in Alzheimer PubMed Google Scholar). MARK4 to with cytoskeletal kinases and and kinase 4 (MARK4) is a of the of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. B. of human protein an protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. phosphorylates microtubule kinase 4 in PubMed Scopus Google Scholar, A. M. M. of kinases by and J. PubMed Scopus Google Scholar, the human Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. J. MARK4 kinase Biol. PubMed Scopus Google Scholar). MARK4 mutation may to the that the accumulation of of MARK4ΔG316E317D and other than or with novel may In to MARK4 to a critical role in other neurodegenerative J. S. M. M. S. Y. A. MARK4 in and tau phosphorylation and Neuropathol. PubMed Scopus Google and D.M. B. Trojanowski J.Q. Lee of microtubule kinases in Neurosci. PubMed Scopus Google Scholar). pathological in MARK4, posttranslational modifications in the linker cause effects to those of the mutation on MARK4 and promote of tau and other of in MARK4ΔG316E317D that promote tau accumulation may into the of MARK4 in the of AD. were in at of transgenic the human at the region and is a from M. B. J. M. in neurodegeneration PubMed Google Scholar). is a from Lu I. Y. Lu B. kinase plays an role in a phosphorylation that tau toxicity in Full Text Full Text PDF PubMed Scopus Google Scholar). human tau alanine at Ser-262 and Ser-356 were K. M. Ohtake Y. Hayashishita M. S. S. Iijima K.M. Tau phosphorylation at Alzheimer's contributes to tau is 2016; PubMed Google Scholar, K. Sekiya M. Maruko-Otake A. Ohtake Y. Suzuki E. Lu B. Iijima K.M. of neurodegeneration and Alzheimer's tau phosphorylation via Genet. 2012; 8 PubMed Scopus Google Scholar). transgenic and human MARK4 was from at mutation was by using was into and into the into of the in the are in tau tau tau and were and are from of were in with and MARK4 were with to the MARK4 in was from the with and protein kinase was using human was and from E. and of into tau was using a for of MARK4, and was using or was using or for in the were to a using a and using was by and was using of were a of with and are for were in the was S. A. Iijima K.M. 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