Tau – Medical Exploration

 

In the mammalian brain, tau appears to be critical for normal neuronal activity.

Tau belongs to the Microtubule-Binding Protein Family,with microtubule-associated proteins (MAP) tau, MAP1 (A/B) and MAP2 being main contributors to microtubule assembly and stability in a mature neuron [1]. 

 

Phosphorylation of tau decreases its efficiency in promoting assembly and stabilising microtubules, with multiple phosphorylation sites having been identified (particularly Ser-Pro or Thr-Pro motifs) [2].

 

Hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases, such as proline-directed MAP and GSK, and tau phosphatases, as well as changes in tau's conformation which affect its interaction with these enzymes [3].

 

Crucially, hyperphosphorylation not only results in loss of function, but also toxic gain of function [2]. Toxic gain of function in taupathies appears to be solely due to its abnormal hyperphosphorylation, because dephosphorylation converts into a normal functional state [1].

 

Affected neurons battle pathological tau by the continuous synthesis of new tau,and packaging the abnormally phosphorylated tau into inert polymers such as neurofibrillary tangles of paired helical filaments (PHF), twisted ribbons and straight filaments (SF) thus causing inhibition and disruption of microtubules. Slowly but progressively, affected neurons endure a retrograde degeneration [1].

 

 Therefore, accumulation of abnormally hyperphosphorylated tau is seen in several human neurodegenerative disorders (see Figure 1), with tau’s causation of Alzheimer's Disease being one of the most widely researched. [1].

 

 

 

 

 

 

 

 

 

 

 

Alzheimer's Disease

 

Since the discovery of tau protein as the major subunit of PHF/SF in neurofibrillary tangles, there has been a considerable interest in understanding the hyperphosphorylation and aggregation of tau into filaments.

 

All 6 tau isoforms (usually found in an adult brain) are present in a hyperphosphorylated state not only neurofibrillary tangles, but also in cytosol from AD brains. The cytosolic hyperphosphorylated tau from AD brain (AD P-tau) contains 5-9 mol of phosphate per mole of the protein, unlike 2-3 in normal tau [1].

 

Tau is unusual compared to other proteins in that it has long stretches of charged (positively and negatively) regions. The predicted amino acids having β-structure in tau (peptides of 36–43 amino acids that are the main constituent of the amyloid plaques ), are concentrated in R2 and R3 and are able to self-assemble into filaments pair helical filaments in vitro [1,2]. Tau self-assembles probably by intermolecular hydrophobic interaction through microtubule binding repeat R3 (in the case of 3R tau), and R2 and R3 (in the case of 4R tau). The way the charged regions are located, it is likely the amino-terminal and carboxyl-terminal regions flanking the repeats have an inhibitory effect upon the self-polymerization of tau. In AD and other taupathies, these inhibitory regions are neutralized by abnormal hyperphosphorylation causing a decrease in the activity of protein phosphatase-2A (PP-2A) and promotion of self-assembly [1].

 

Frontotemporal Dementia

 

In frontotemporal dementia, inherited missense mutations linked to chromosome-17 (FTDP-17) crucially alter the conformation of tau such that it become more favourable substrate to brain protein kinases, compared to wild-type tau, and are is more rapidly phosphorylated. G272V, P301L, V337M and R406W are the most studied missense mutations [1]. Additionally, mutated tau proteins can self-assemble into filaments at a lower level of phosphorylation ,compared to wild-type tau (see Figure 2) , leading to neurofibrillary degeneration and dementia [1,3].

 

Studies into frontotemporal dementia have helped establish, that tau abnormalities as an initial event can lead to neurodegeneration. Therefore, inhibition of this tau abnormality is one of the most promising areas regarding treatment of AD and other taupathies.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References

 

​1. http://www.ncbi.nlm.nih.gov/pubmed/15615638

​2. http://www.ncbi.nlm.nih.gov/pubmed/22595282

3. http://www.ncbi.nlm.nih.gov/pubmed/10967355

4. http://www.ncbi.nlm.nih.gov/pubmed/1376245