Lysine-Directed Post-translational Modifications of Tau Protein in Alzheimer's Disease and Related Tauopathies

Abstract

Tau is a microtubule-associated protein responsible mainly for stabilizing the neuronal microtubule network in the brain. Under normal conditions, tau is highly soluble and adopts an “unfolded” conformation. However, it undergoes conformational changes resulting in a less soluble form with weakened microtubule stabilizing properties. Altered tau forms characteristic pathogenic inclusions in Alzheimer's disease and related tauopathies. Although, tau hyperphosphorylation is widely considered to be the major trigger of tau malfunction, tau undergoes several post-translational modifications at lysine residues including acetylation, methylation, ubiquitylation, SUMOylation, and glycation. We are only beginning to define the site-specific impact of each type of lysine modification on tau biology as well as the possible interplay between them, but, like phosphorylation, these modifications are likely to play critical roles in tau's normal and pathobiology. This review summarizes the latest findings focusing on lysine post-translational modifications that occur at both endogenous tau protein and pathological tau forms in AD and other tauopathies. In addition, it highlights the significance of a site-dependent approach of studying tau post-translational modifications under normal and pathological conditions.

Endolysosomal degradation of Tau and its role in glucocorticoid‐driven hippocampal malfunction

“…The current study demonstrates that GC impair Tau degradation by downregulating Rab35, thereby suppressing Tau sorting into the ESCRT pathway and leading to the accumulation of ubiquitylated Tau (Fig 7). These results support the concept that ubiquitylation, the major signal for cargo sorting into the ESCRT pathway, represents the first line of cellular defense against Tau accumulation and related neuronal malfunction (Chesser et al, 2013;Kontaxi et al, 2017). Importantly, we find that Rab35 overexpression blocks Tau accumulation and neuronal atrophy induced by high GC levels.…”

Quantitative Analysis of the Brain Ubiquitylome in Alzheimer's Disease

“…Crosstalk between PTMs is hypothesized to add complexity to cellular homeostasis regulatory processes . The role of complex PTMs on Tau protein aggregation is evidenced by crosstalk between phosphorylation and acetylation . The MTBR of Tau has four KXGS motifs and competition between phosphorylation (on serine) and acetylation (on lysine) within this motif has been reported .…”

“…This indicates that crosstalk between phosphorylation and ubiquitylation also occurs within this motif on Tau (Figure B). Besides phosphorylation and ubiquitylation, lysine residues in Tau have been reported to undergo multiple PTMs including acetylation, glycation, methylation, and SUMOlyation . Future studies are needed to characterize potential relationship between phosphorylation and these lysine modifications on Tau protein function.…”

“…[54] The role of complex PTMs on Tau protein aggregation is evidenced by crosstalk between phosphorylation and acetylation. [15,55] The MTBR of Tau has four KXGS motifs and competition between phosphorylation (on serine) and acetylation (on lysine) within this motif has been reported. [17] Hypoacetylation within KXGS motifs is associated with hyperphosphorylation and increased Tau aggregation.…”

“…Besides phosphorylation and ubiquitylation, lysine residues in Tau have been reported to undergo multiple PTMs including acetylation, [18,56] glycation, [57] methylation, [58] and SUMOlyation. [55] Future studies are needed to characterize potential relationship between phosphorylation and these lysine modifications on Tau protein function. GO enrichment analysis on co-modified gene products mapped to a wide variety of biological processes including: ubiquitin-specific protease activity, G1/S transition of mitotic cell cycle, and macromolecule catabolic processes (Table S8, Supporting Information).…”