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 Ser262 and Ser356 play 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 Ser262/356-dependent and -independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that co-expression 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 Ser262 and Ser356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, while co-expression 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 impact disease pathogenesis.

Axonal plasticity in response to active forces generated through magnetic nanopulling

“…We focused on TAU for the following reasons: i) TAU phosphorylation influences MT assembly (Kadavath et al, 2015); ii) re-positioning of TAU was already found in response to force (Kunze et al, 2015); iii) we found a down-regulation of the kinase microtubule affinity-regulating kinase 4 (MARK4) that phosphorylates TAU on Ser-262 via Axon-seq. The phosphorylation of TAU in Ser-262 residue considerably reduces its binding to MTs, causing MT destabilization (Biernat et al, 1993; Oba et al, 2020; Sengupta et al, 1998). Conversely, when TAU is dephosphorylated, it may promote MT assembly (Lindwall and Cole, 1984; Liu et al, 2007; Scott et al, 1993).…”

Integration of multidimensional splicing data and GWAS summary statistics for risk gene discovery

“…Among genes that could only be identified using splicing data, PICALM (MSG p -value = 1.93 × 10 −9 ; S-PrediXcan p -value = 9.80 × 10 −1 ) and PTK2B (MSG p -value = 7.96 × 10 −9 ; S-PrediXcan p -value = 8.98 × 10 −1 ) are two genes previously shown to be significantly differentially spliced between AD patients and healthy controls [ 17 ]. MARK4 (MSG p -value = 1.31 × 10 −58 ; S-PrediXcan p -value = 8.48 × 10 −2 ) was shown to change the properties of tau [ 34 ] and has variants reported to be associated with AD and AD family history [ 35 , 36 ]. Several genes in the APOE region are also significant in splicing but not in expression analysis: APOE (MSG p -value = 1.12 × 10 −8 ; S-PrediXcan p -value = 2.49 × 10 −3 ) is a well-known risk gene [ 37 ] for late-onset AD, with reports that alternative splicing (exclusion of exon 5) is associated with increased beta-amyloid deposition, and affects tau structure [ 38 ]; APOC1 (MSG p -value = 4.65 × 10 −17 ; S-PrediXcan p -value = 2.07 × 10 −3 ) has been reported to be associated with family history of AD [ 39 , 40 ]; TOMM40 (MSG p -value = 5.67 × 10 −9 ; S-PrediXcan p -value = 4.84 × 10 −1 ) has been reported to have intronic variants associated with family history of AD [ 35 ] and high density lipoprotein cholesterol (HDL-C) levels [ 41 ]; ERCC1 (MSG p -value = 2.32 × 10 −27 ; S-PrediXcan p -value = 4.48 × 10 −2 ), a DNA repair enzyme, has been shown to be associated with the quantification of amount of tau and implicated in AD [ 42 ].…”

Integration of multidimensional splicing data and GWAS summary statistics for risk gene discovery

“…MARK4 (MSG p-value = 1.31 × 10 −58 ; S-PrediXcan p-value = 8.48 × 10 −2 ) was shown to change the properties of tau [32] and has variants reported to be associated with AD and AD family history [33,34]. Several genes in the APOE region are also significant in September 5, 2021 6/23 splicing but not in expression analysis: APOE (MSG p-value = 1.12 × 10 −8 ; S-PrediXcan p-value = 2.49 × 10 −3 ) is a well-known risk gene [35] for late-onset AD, with reports that alternative splicing (exclusion of exon 5) is associated with increased beta-amyloid deposition, and affects tau structure [36]; APOC1 (MSG p-value = 4.65 × 10 −17 ; S-PrediXcan p-value = 2.07 × 10 −3 ) has been reported to be associated with family history of AD [37,38]; TOMM40 (MSG p-value = 5.67 × 10 −9 ; S-PrediXcan p-value = 4.84 × 10 −1 ) has been reported to have intronic variants associated with family history of AD [33] and high density lipoprotein cholesterol (HDL-C) levels [39]; ERCC1 (MSG p-value = 2.32 × 10 −27 ; S-PrediXcan p-value = 4.48 × 10 −2 ), a DNA repair enzyme, has been shown to be associated with the quantification of amount of tau and implicated in AD [40].…”