Alzheimer’s Disease: The two shapes of the Tau protein

Tau proteins can convert from an inert shape to a misfolded shape that seeds the growth of fibers that contribute to the pathology of Alzheimer's disease.
  1. Jeffery W Kelly  Is a corresponding author
  1. The Scripps Research Institute, United States

Most of the time, proteins fold into a single stable shape to perform their role in the body, but occasionally they can adopt a different conformation. These 'misfolded' proteins can be associated with a range of degenerative conditions known as amyloid disorders, which includes the transthyretin amyloidoses as well as Alzheimer’s and Parkinson's diseases. This is because the misfolded proteins go on to stick together and form toxic insoluble aggregates, for example ‘amyloid’ fibers, that accumulate inside cells. One such protein is Tau, which aggregates in people with Alzheimer’s disease. It is thought that the misfolded Tau proteins and the various Tau aggregates, including amyloid fibers, contribute to the onset of Alzheimer’s disease (Eisele et al., 2015), but these processes are not fully understood.

Inside a cell, the harmful aggregation process is believed to begin with a ‘seed’, a template that can trigger the assembly of a given protein. These seeds are thought to be crucial in the spread of the disease. The hypothesis is that seeds can convert the normally folded protein into an aggregate of the same protein, before cells release them into the environment for neighboring cells to take up (Eisenberg and Jucker, 2012). This could be how diseases linked to the Tau protein, such as Alzheimer’s, propagate from one cell to another; there, the aggregates would travel through the brain using the connections between neurons (Clavaguera et al., 2009; Sanders et al., 2014). While the identity of the seeds remains unclear, until now, almost all scientists have believed that they are an assembly of a given individual misfolded protein. Now, in eLife, Marc Diamond of the University of Texas Southwestern Medical Center (UTSW) and colleagues – including Hilda Mirbaha as first author – report the existence of a stable of form of an individual Tau protein that can start the aggregation process on its own (Mirbaha et al., 2018).

The fact that the seed may not be an assembly of a misfolded protein, but instead be a single protein – a monomer – with a different conformation had only been suggested twice before. In 2005, a study proposed that a change in the conformation of a Tau monomer had a critical role in triggering the process of aggregation (Chirita et al., 2005). And in 2011, it was hypothesized that the aggregation of the huntingtin protein, which is involved in another amyloid disorder known as Huntington’s disease, could start with a single protein (Kar et al., 2011). However, in these two studies the monomer that could initiate the seeding process was not isolated and studied. Despite robust data interpretation, many in the scientific community dismissed the idea of monomeric seeds, reluctant to challenge the widely ingrained concept that they are instead an assembly of a misfolded protein.

So far, Tau was considered to be an intrinsically disordered protein – more like a flexible noodle than a protein with a well-defined and stable, three-dimensional structure (Schweers et al., 1994). Instead, Mirbaha et al. show that the Tau protein can fold into two distinct and fairly well-defined conformations. One of these shapes is stable, nontoxic and does not easily aggregate; the other acts as a seed and can help to convert another ‘harmless’ Tau monomer into a misfolded Tau that will form toxic aggregates by seeding or self-assembly. In addition, Tau can very slowly change from the inert to the seed-competent conformation. It is known that small molecules can bind to the inert conformation of proteins that are prone to misfolding, and thus prevent the conformational change that leads to amyloid diseases (Johnson et al., 2012).

For example, transthyretin is another protein with two ways of folding, and whose toxic conformation damages various nervous systems, as well as the heart. However, drugs known as kinetic stabilizers can slow down the degenerative process by increasing the population of the properly folded conformation. More precisely, three placebo-controlled clinical trials showed that small molecules, such as the drugs tafamidis and diflunisal, can bind to the non-pathogenic form of transthyretin and stabilize it, which prevents the protein from converting into the conformation that initiates aggregates and leads to degenerative pathologies (Coelho et al., 2012; Berk et al., 2013; Rosenblum et al., 2018). This suggests that it should be possible to fashion similar kinetic stabilizers for the Tau protein, and offer better treatment for diseases such as Alzheimer’s.

References

    1. Schweers O
    2. Schönbrunn-Hanebeck E
    3. Marx A
    4. Mandelkow E
    (1994)
    Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure
    The Journal of Biological Chemistry 269:24290–24297.

Article and author information

Author details

  1. Jeffery W Kelly

    Jeffery W Kelly is in the Departments of Chemistry and Molecular Medicine, The Scripps Research Institute, La Jolla, United States

    For correspondence
    jkelly@scripps.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8943-3395

Publication history

  1. Version of Record published: July 10, 2018 (version 1)

Copyright

© 2018, Kelly

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,366
    Page views
  • 514
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jeffery W Kelly
(2018)
Alzheimer’s Disease: The two shapes of the Tau protein
eLife 7:e38516.
https://doi.org/10.7554/eLife.38516

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Dirk H Siepe, Lukas T Henneberg ... Kenan Christopher Garcia
    Tools and Resources

    Secreted proteins, which include cytokines, hormones and growth factors, are extracellular ligands that control key signaling pathways mediating cell-cell communication within and between tissues and organs. Many drugs target secreted ligands and their cell-surface receptors. Still, there are hundreds of secreted human proteins that either have no identified receptors ('orphans') and are likely to act through cell surface receptors that have not yet been characterized. Discovery of secreted ligand-receptor interactions by high-throughput screening has been problematic, because the most commonly used high-throughput methods for protein-protein interaction (PPI) screening do not work well for extracellular interactions. Cell-based screening is a promising technology for definition of new ligand-receptor interactions, because multimerized ligands can enrich for cells expressing low affinity cell-surface receptors, and such methods do not require purification of receptor extracellular domains. Here, we present a proteo-genomic cell-based CRISPR activation (CRISPRa) enrichment screening platform employing customized pooled cell surface receptor sgRNA libraries in combination with a magnetic bead selection-based enrichment workflow for rapid, parallel ligand-receptor deorphanization. We curated 80 potentially high value orphan secreted proteins and ultimately screened 20 secreted ligands against two cell sgRNA libraries with targeted expression of all single-pass (TM1) or multi-pass (TM2+) receptors by CRISPRa. We identified previously unknown interactions in 12 of these screens, and validated several of them using surface plasmon resonance and/or cell binding. The newly deorphanized ligands include three receptor tyrosine phosphatase (RPTP) ligands and a chemokine like protein that binds to killer cell inhibitory receptors (KIR's). These new interactions provide a resource for future investigations of interactions between the human secreted and membrane proteomes.

    1. Biochemistry and Chemical Biology
    Meiling Wu, Anda Zhao ... Dongyun Shi
    Research Article

    Antioxidant intervention is considered to inhibit reactive oxygen species (ROS) and alleviates hyperglycemia. Paradoxically, moderate exercise can produce ROS to improve diabetes. The exact redox mechanism of these two different approaches remains largely unclear. Here, by comparing exercise and antioxidants intervention on type 2 diabetic rats, we found moderate exercise upregulated compensatory antioxidant capability and reached a higher level of redox balance in the liver. In contrast, antioxidant intervention achieved a low-level redox balance by inhibiting oxidative stress. Both of these two interventions could promote glucose catabolism and inhibit gluconeogenesis through activation of hepatic AMPK signaling, therefore ameliorating diabetes. During exercise, different levels of ROS generated by exercise have differential regulations on the activity and expression of hepatic AMPK. Moderate exercise-derived ROS promoted hepatic AMPK glutathionylation activation. However, excessive exercise increased oxidative damage and inhibited the activity and expression of AMPK. Overall, our results illustrate that both exercise and antioxidant intervention improve blood glucose in diabetes by promoting redox balance, despite different levels of redox balance. These results indicate that the AMPK signaling activation, combined with oxidative damage markers, could act as a sensitive biomarker, reflecting the threshold of redox balance defining effective treatment in diabetes. These findings provide theoretical evidence for the precise treatment of diabetes by antioxidants and exercise.