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.
Highlights
Neurodegenerative diseases of the central nervous system are characterized by selective loss of synapses and neurons, glial activation, progressive irreversible neural dysfunction, cognitive impairment and eventually death (Verkhratsky et al, 2014; Kovacs, 2016)
It is polyubiquitylation rather than the attachment of a single ubiquitin that acts to induce the proteolytic degradation of targeted proteins in the cytoplasm by the ubiquitin-proteasome system (UPS), but different types of polyubiquitin linkage affect the fate of the modified protein in various ways
Mass spectrometric analysis of soluble paired helical filaments (PHFs)-tau immunopurified from Alzheimer’s disease (AD) brains revealed three putative ubiquitylated lysine residues: K254 and K353 located in the R1 and R4 repeat sequences, respectively, and K311 found in the flanking region between the R2 and R3 repeat sequences (Figure 3C; Cripps et al, 2006)
Summary
Neurodegenerative diseases of the central nervous system are characterized by selective loss of synapses and neurons, glial activation, progressive irreversible neural dysfunction, cognitive impairment and eventually death (Verkhratsky et al, 2014; Kovacs, 2016). Many neurodegenerative diseases are known as conformational diseases- or proteinopathies-due to the presence of pathological forms of proteins that accumulate and deposit in the brain (Carrell and Lomas, 1997). For this reason, it has been assumed that the aggregation of misfolded proteins is the molecular cause of neurodegeneration. In AD, tau lesions include neurofibrillary tangles (NFTs) in neuronal cell bodies, neuropil threads in neurites and dystrophic neurites in neuritic plaques; in electron microscopy, tau assemblies form mainly paired helical filaments (PHFs) that consist of both 3R and 4R isoforms (Figure 1B). It emphasizes the need to achieve a complete understanding of the biological role of lysine site-specific modifications in both endogenous and aggregated tau, in order to shed light on the molecular events underlying the pathological transition of tau that characterizes tau-mediated neurodegeneration
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