Alzheimer  >   5. The Tau Protein

Tau is one of several types of microtubule-associated proteins (MAPs). Although microtubules exist in all kinds of animal and plant cells, Tau is present only in neurons and predominantly localized to axons, suggesting that Tau could play special roles in neurons. A few neurodegenerative disorders have been found to arise from abnormality in the Tau protein, including Alzheimer's disease, Huntington's disease, frontotemporal dementia and progressive supranuclear palsy. Tau is also implicated in other neurodegenerative disorders such as Parkinson's disease and amyotrophic lateral sclerosis.

Tau Isoforms

Tau is encoded by a single gene, MAPT, which may generate six isoforms through alternative RNA splicing. They differ in the number of inserts at the N-terminal half and the number of repeats in the microtubule binding domain (Figure 5-1). A Tau isoform is commonly designated as xNyR, where x is the number of inserts and y is the number of repeats. For instance, 2N4R indicates that it contains two N-terminal inserts and four repeats. The number of inserts can be 0, 1 or 2 and the number of repeats may be either 3 or 4. The 4-repeat (4R) Tau includes the second repeat encoded by exon 10.


Figure 5-1. Tau isoforms generated by alternative splicing. The longest Tau (2N4R) consists of 441 amino acids while the shortest Tau (0N3R) has 352 amino acids. MTBD: microtubule binding domain. [Source: Guo et al., 2017]

The 4R-Tau binds to, assembles, and stabilizes microtubules more effectively than 3R-Tau (Bunker et al., 2004). In a healthy adult brain, the levels of 4R- and 3R-Tau proteins are approximately equal. Elevation of total and/or 4R-Tau is prone to develop Alzheimer's disease and other neurodegenerative disorders.

Amino Acid Sequence

The longest isoform has 441 amino acids containing 56 negative residues (D or E). Most of them are located in the first 150 residues (Figure 5-2).


Figure 5-2. The amino acid sequence of the longest isoform of Tau protein. [Source: Mukrasch et al., 2009.]

Paperclip Conformation

In a normal free Tau, both N and C termini fold back such that they are in close proximity (Jeganathan et al., 2006). This structure is known as the "paperclip conformation" (Figure 5-3). PAD stands for "phosphatase-activating domain", comprising amino acids 2 -18. It plays a central role in the pathology caused by the Tau protein. Briefly, in the paperclip conformation, the C-terminal domain prevents PAD from interacting with its major target, protein phosphatase 1 (PP1). If the N-terminal domain moves away from the C-terminal domain, PAD would be exposed to PP1. In this case, PAD may activate PP1, which in turn will activate glycogen synthase kinase-3 (GSK-3). Further details are described in the next chapter.


Figure 5-3. The paperclip conformation of Tau. In this conformation, PAD is inaccessible to its major target, protein phosphatase 1 (PP1). Aberrant exposure of PAD to PP1 may cause Tau pathology. [Adapted from: Guo et al., 2017]

Phosphorylation Sites

Phosphorylation is a process that adds a negatively charged phosphate group (PO43−) to a protein, particularly on the amino acid serine, threonine or tyrosine. It is catalyzed by a special class of enzymes called "protein kinases". The most important protein kinase involved in neurodegeneration is GSK-3β, as hyperactive GSK-3β may impair axonal transport, neurite growth and long-range synchronization (see this article).

Dephosphorylation removes the phosphate group from a protein. The enzymes catalyzing dephosphorylation is called "phosphatase" such as PP1, which may activate GSK-3β by dephosphorylation at serine-9.

The longest isoform of Tau contains more than 60 potential phosphorylation sites. Among them, five are tyrosine residues, which exist in all isoforms. They are located at 18, 29, 197, 310 and 394 (numbering is based on the longest isoform). The tyrosine kinase Fyn preferentially targets tyrosine-18 (Y18) - the last residue of PAD. Y18 is phosphorylated in the AD brain and at early developmental stages in mice, but not in healthy adult (Lee et al., 2004). Phosphorylation at Y18 could prevent PAD from activating PP1 (Kanaan et al., 2012).

Serine-262 (S262) is located in the first repeat of the microtubule binding domain (Figure 5-2). Phosphorylation on this residue causes Tau to detach from microtubules (Schneider et al., 1999). This site can be phosphorylated by protein kinase A (PKA) and calmodulin-dependent protein kinase II (CaMKII). Interestingly, GSK-3β does not phosphorylate S262, although it targes over a dozen Tau sites, including S199, S202, threonine-205 (T205), S396 and S404 (Wang et al., 2007). Phosphorylation at S199, S202, and T205 could move the N-terminal domain away from the C-terminal domain while phosphorylation at S396 and S404 could move the C-terminal domain away from the repeat domain, as demonstrated by pseudo-phosphorylation in which these residues are mutated to negatively charged glutamate (E) (Jeganathan et al., 2008). Hence, GSK-3β could promote PAD exposure to PP1 and further augment GSK-3β activity. The next chapter will present evidence to corroborate the idea that the PAD/PP1/GSK-3β pathway is at the heart of Tau pathology.


Author: Frank Lee
Last updated: June 18, 2019