Tau is a highly soluble protein that mainly expressed in the neurons in the central nervous system (CNS), and it also distributes in glial cells such as oligodendrocytes and astrocytes in the CNS, as well as peripheral nervous system (PNS). Firstly discovered as a microtubule-associated protein (MAP) in 1975, Tau protein is primarily found in axons where it regulates microtubule polymerization and promotes microtubule stabilization. However, via the selective binding of diverse partners, Tau participates in multiple physiological processes including regulation of axonal diameter and growth, regulation of vesicle and organelle transport, modulation of signaling cascades by acting as a protein scaffold, cellular response to heat shock, adult neurogenesis and the establishment of neuronal polarity in development. Otherwise, abnormal Tau functions are deeply involved in neurodegenerative diseases such as Alzheimer's disease (AD).
Tau protein is produced by alternative mRNA splicing of a single gene MAPT. Human MAPT is located at the chromosomal locus 17q21 and contains 16 exons, and alternative splicing of exons 2, 3, and 10 yields six isoforms. The structure of tau protein is divided into four regions: an acidic N-terminal region, a proline-rich region, a microtubule-binding domain (MBD) that is responsible for tau binding to microtubules and a C-terminal region. The MBD of Tau contains four repeat domains known as microtubule binding repeats R1, R2, R3 and R4, each of which contains a conserved consensus motif KXGS that can be phosphorylated at serine, resulting in the destabilization of the neuronal cytoskeleton.
Figure 1. Schematic diagram showing the organization of the six predominant isoforms of tau found in adult human brain. (Gail, et al. 2004)
Phosphorylation, a process of addition of a phosphate group to amino acids, is the most common post-translational modification of tau protein, which affects its solubility, localization, function, interaction with partners and susceptibility to other post-translational modifications. Tau protein contains 85 putative serine (S), threonine (T), and tyrosine (Y) phosphorylation sites, among which, 28 are exclusively phosphorylated in AD brains, 16 are phosphorylated both in AD and in control brains, 31 are phosphorylated in physiological conditions and 10 are tau putative phosphorylation sites without an identified kinase.
A large amount of Tau protein kinases have been described, and can be subdivided into three classes: proline-directed protein kinases (PDPKs), protein kinases non-PDPKs and tyrosine protein kinases (TPKs). Additionally, several phosphatases dephosphorylate Tau, including protein phosphatase-1, -2A, and -5 (PP1, PP2A, and PP5).
Table 1. Example of Tau protein kinases
Glycogen Synthase Kinase 3 (GSK3),
Cyclin-Dependent Kinase 5 (Cdk5),
5' Adenosine Monophosphate-Activated Protein Kinase (AMPK)
Casein Kinase 1 (CK1),
Microtubule Affinity-Regulating Kinases (Marks),
Cyclic AMP-Dependent Protein Kinase A (PKA),
Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK-1A)
|TPK||Fyn, Abl, Syk|
GSK3 contains two isoforms α and β, they are encoded by different genes but share approximately 85% sequence homology. Phosphorylation at serine residue 21 on GSK3α, serine residues 9 and 389 on GSK3β inhibits its activity (inactive status), whereas phosphorylation at tyrosine 279 on GSK3α and at tyrosine 216 on GSK3β isoform increases GSK3 activity (active status). Several protein kinases catalyze the phosphorylation of GSK3, such as cAMP-dependent (PKA), protein kinase B (PKB, also known as Akt), p70S6K/p85S6 kinase, p90-ribosomal S6 kinase. The P70S6K/p85S6 kinase and p90-ribosomal S6 kinase can be activated in response to Akt/PKB and mitogen-activated protein kinase (MAPK), respectively. Calcium is also a regulator of GSK3β activity. A modest, transient increase in intracellular calcium can cause an increase in phosphorylation at tyrosine 216, which is believed to contribute to a prolonged increase in GSK3-dependent Tau phosphorylation. According to GSK3 status, GSK3 regulates several signaling pathways including insulin, nuclear factor (NF)-κB, Wnt/β-catenin and tyrosine kinase receptor (TKR) pathways. In addition, GSK3 is also known to be involved in cell proliferation, neural functions, apoptosis, oncogenesis, embryonic development, and immune response.
Cdk5 belongs to the cyclin-dependent kinase family, however, it does not participate in cell cycle regulation. Cdk5 works with its co-activators p35 and p25, which is a truncated form of p35. The activity of neuronal Cdk5, therefore, is dependent on the selective expression of the co-activators in the cells. Without this interaction, the monomeric form of CDK5 is enzymatically inactive. Cdk5/p35 complex plays a predominant role in brain development and function, while Cdk5/p25 complex (the most active form of Cdk5) is able to phosphorylate Tau protein at 11 sites that are found in AD brains. CDK5 is essential for the development of CNS and is involved in the regulation of neuronal cytoskeleton dynamic, neuritic outgrowth, neuronal apoptosis, and synaptic functions.
Tau Hyperphosphorylation & Aggregation
Under physiological conditions, Tau phosphorylation supports to maintain cytoskeletal structure. However, increased Tau phosphorylation, or Tau hyperphosphorylation, reduces its affinity for microtubules leading to cytoskeletal destabilization. Excessively phosphorylated Tau accumulates in the somatodendritic compartment of neurons, forms Tau oligomers, aggregates to make up the paired helical filaments (PHFs) and eventually develops neurofibrillary tangles (NFTs). NFTs are a key contributor to neuronal dysfunction, especially marking axonal degeneration, which plays an important role in neurodegenerative diseases pathology.
Figure 2. Diagram of Tau hyperphosporylation and Tau pathology. (Gail, et al. 2004)
|1.||Johnson G V W, Stoothoff W H. Tau phosphorylation in neuronal cell function and dysfunction. Journal of cell science, 2004, 117(24): 5721-5729.|
|2.||Martin L, Latypova X, Wilson C M, et al. Tau protein kinases: involvement in Alzheimer's disease. Ageing research reviews, 2013, 12(1): 289-309.|
|3.||Mietelska-Porowska A, Wasik U, Goras M, et al. Tau protein modifications and interactions: their role in function and dysfunction. International journal of molecular sciences, 2014, 15(3): 4671-4713.|
|4.||Stoothoff W H, Johnson G V W. Tau phosphorylation: physiological and pathological consequences. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2005, 1739(2): 280-297.|