ReviewTau protein kinases: Involvement in Alzheimer's disease
Highlights
► The causes of tau phosphorylation in tauopathies like Alzheimer's disease are still uncovered. ► Tau phosphorylation could be to the origin of Alzheimer's disease. ► Tau kinases dysfunctions might contributes to tau phosphorylation. ► Knowledge of the relative importance of tau kinases allows to elaborate protection strategies against AD. ► The most common inhibitory compounds acting on each tau kinase are described.
Introduction
Alzheimer's disease (AD) (Alzheimer, 1907) is a neurodegenerative pathology which is characterized by the presence of two types of neuropathological hallmarks: neurofibrillary tangles (NFT) and senile plaques (SP) (Kidd, 1963). NFT are intraneuronal aggregations mainly composed of abnormally phosphorylated tau. SP are extracellular and the major component of these lesions is β-amyloid (Aβ) peptide. The molecular and cellular mechanisms responsible for the formation of these lesions remain unclear and it is still controversial whether these lesions are a primary causative factor or play a more peripheral role in the disease. Several tau post-translational modifications were proposed to play an important role in tau aggregation linked to AD (reviewed by Martin et al., 2011a). Among these post-translational modifications, phosphorylation is the major modification with 85 putative sites. In AD, tau phosphorylation precedes tau aggregation into NFT (reviewed by Avila, 2006).
Tau phosphorylation is regulated by a balance between tau kinase and phosphatase activities. Disruption of this equilibrium was suggested to be at the origin of abnormal tau phosphorylation and thereby contributes to tau aggregation. Thus, understanding the regulation modes of tau phosphorylation is of high interest in determining the possibly involved causes in formation of tau aggregates and to elaborate protection strategies to cope with these lesions in AD. Inhibition of specific tau kinases is one of the strategies reversing tau phosphorylation. Here, we extensively reviewed tau protein kinases, their physiological roles and regulation, their involvement in tau phosphorylation and their relevance to AD. We also reviewed the most common inhibitory compounds acting on each tau kinase.
Section snippets
Tau protein
Tau protein is a microtubule-associated protein mainly expressed in neurons and plays a crucial role in the neuronal cytoskeleton stabilization. The structure of tau protein is subdivided into four regions: an acidic region in the N-terminal part, a proline-rich region, a region responsible for tau binding to microtubules, containing four repeat domains R1, R2, R3 and R4 also called microtubule-binding domains (MBD) (Drewes et al., 1995, Sengupta et al., 1998; reviewed by Gendron & Petrucelli,
Tau protein kinases
Kinases belong to the enzyme group termed “transferases” because they transfer phosphate group from high-energy donor molecules, such as ATP or GTP, to specific substrates. The catalytic core, where phosphorylation reaction occurs, is conserved among kinases. This functionally active domain contain an ATP/GTP binding pocket and a fixation site where the substrate to be phosphorylated is maintained. When the energy donor and the substrate are anchored to the kinase, phosphate transfer occurs.
Quantitative and qualitative contributions of distinct kinases to tau phosphorylation in AD
Tau protein is constituted in 85 putative phosphorylation sites: 26 sites are located in the acidic region, 26 sites in the proline rich-region, 16 sites in the repeat domain region and 17 sites in the C-terminal extremity (Fig. 3).
To evaluate the importance of each kinase in tau phosphorylation, we generated a tau kinase pyramid where the physiological and pathological phosphorylation sites (sites found phosphorylated in AD brains) were included (Fig. 3). Tau kinase pyramid indicates that
Concluding remarks
This review focuses on the diversity of tau kinases involved in AD and their effectiveness on various tau phosphorylation sites. Although pyramid scheme is perfectible with future studies, so far, it is impossible to decipher which one of tau phosphorylation sites were studied and not revealed in publications. Probably, a future systematic analysis for each kinase included in pyramid will be very interesting. The interconnections between various tau protein kinases (and probably tau protein
Conflicts of interest
The authors declare that they have no financial interest for all listed compounds.
Acknowledgements
This work was supported by the University of Nantes, University of Limoges, INSERM and the “Conseil Régional du Limousin”, France.
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