ReviewPost-translational modifications of tau protein: Implications for Alzheimer's disease
Graphical abstract
Model for interconnections between tau post-translational modification and regulation of NFT formation. Cellular mechanisms that impact tau aggregation into NFTs are subdivided into two categories: pro-aggregation and anti-aggregation mechanisms. This model integrates direct and indirect impacts of Aβ, GSK3β, PP2A, Pin1 and ubiquitin-proteasome system (UPS) on the formation of NFTs.
Research highlights
▶ The causes of tau aggregation in Alzheimer's (AD) disease are still uncovered. ▶ Tau phosphorylation was suggested to play a central role in tau aggregation. ▶ However, tau phosphorylation alone is not sufficient to induce tau aggregation. ▶ Other tau post-translational modifications seem to be involved in tau aggregation. ▶ Here, we review all tau post-translational modifications and their relevance for AD.
Introduction
Alzheimer's disease (AD) (Alzheimer, 1907) is a neurodegenerative disease which is characterized by the presence of two types of neuropathological hallmarks: neurofibrillary tangles (NFTs) and senile plaques. NFTs are intraneuronal aggregates of abnormally phosphorylated tau (phosphorylated at non physiological sites). Senile plaques are extracellular and mainly composed of amyloid β-peptide (Aβ) deposits.
To aggregate into PHFs (paired helical filaments), tau affinity for microtubules must be decreased to release tau in a soluble form. Dissociation of tau from microtubules, probably by phosphorylation, results in microtubule destabilization. For example, tau pseudophosphorylation at specific sites such as S262, S293, S324 and S356 (pseudophosphorylation is achieved by replacing a phosphorylation site with glutamic acid or aspartic acid) was reported to induce tau conformational change and attenuate tau binding to microtubules (Fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process and constitute subunits of filaments, called protomers. Two protomers around each other formed PHFs and PHFs assembly make NFTs (Fig. 1) (see Meraz-Rios et al., 2010 for an extensive review).
The molecular and cellular mechanisms responsible for the formation of tau lesions remain unclear. Although, it is still controversial whether these lesions are a primary causative factor or play a peripheral role in the disease, understanding the regulation modes of tau is of high interest in determining the possible causes at the origin of the formation of tau aggregates and to elaborate protection strategies to cope with these lesions. Tau phosphorylation is the most common post-translational modification and abnormalities in tau phosphorylation were proposed to play a crucial role in tau aggregation. Since tau phosphorylation is not constantly accompanied by its aggregation, it is likely that additional post-translational modifications are required for the formation of tau aggregates. Here, we review post-translational modifications of tau with a particular interest towards their relevance in AD.
Section snippets
Tau gene, mRNA and protein structures
Tau protein (tubulin-associated unit) was identified in 1975 (Cleveland et al., 1977, Weingarten et al., 1975). Tau is a microtubule-associated protein highly conserved and exclusively found in higher eukaryotes (Cambiazo et al., 1995, Goedert et al., 1989, Goedert et al., 1996). Tau is mainly expressed in neuron and its primary role, by interacting with microtubules, is to stabilize neuronal cytoskeleton. Tau is encoded by a single gene located in locus 17q21.3 in human (Almos et al., 2008,
Tau phosphorylation
Protein phosphorylation is the addition of a phosphate group by esterification at three types of amino acids: serine (S), threonine (T) and tyrosine (Y). Phosphorylation is the most common tau post-translational modification described. It is widely admitted that an increase in tau phosphorylation reduces its affinity for microtubules which results in neuronal cytoskeleton destabilization. Among the 85 putative phosphorylation sites on tau (Fig. 3, Fig. 4; Table 1), 45 are serines (53% of
Interactions between tau post-translational modifications
To date, it is difficult to define which of the described tau post-translational modifications are preferentially implicated in tau pathology. Certainly, cooperation between several tau post-translational modifications is required for tau aggregation into NFTs. According to the number of sites involved, tau phosphorylation may be considered as the major tau post-translational modification (85 sites), whereas the number of sites involved in the other tau post-translational modifications is low
Conclusions and future directions
Tau hyperphosphorylation seems to be required, but is not sufficient alone, to induce tau aggregation, other (less investigated) tau post-translational modifications are certainly required. Due to our better understanding of the mechanisms of tau phosphorylation and to its quantitative importance (85 phosphorylation sites), targeting, tau phosphorylation by inhibiting tau kinases seems today the most feasible strategy to prevent tau aggregation and associated pathological effects. However, tau
Acknowledgements
This work was supported by the University of Limoges and the “Conseil Régional du Limousin”, France. We greatly thank Dr Cornelia Wilson for editing this manuscript.
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