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

  • 4,562
    Page views
  • 525
    Downloads
  • 3
    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. Plant Biology
    Dietmar Funck, Malte Sinn ... Jörg S Hartig
    Research Article

    Metabolism and biological functions of the nitrogen-rich compound guanidine have long been neglected. The discovery of four classes of guanidine-sensing riboswitches and two pathways for guanidine degradation in bacteria hint at widespread sources of unconjugated guanidine in nature. So far, only three enzymes from a narrow range of bacteria and fungi have been shown to produce guanidine, with the ethylene-forming enzyme (EFE) as the most prominent example. Here, we show that a related class of Fe2+- and 2-oxoglutarate-dependent dioxygenases (2-ODD-C23) highly conserved among plants and algae catalyze the hydroxylation of homoarginine at the C6-position. Spontaneous decay of 6-hydroxyhomoarginine yields guanidine and 2-aminoadipate-6-semialdehyde. The latter can be reduced to pipecolate by pyrroline-5-carboxylate reductase but more likely is oxidized to aminoadipate by aldehyde dehydrogenase ALDH7B in vivo. Arabidopsis has three 2-ODD-C23 isoforms, among which Din11 is unusual because it also accepted arginine as substrate, which was not the case for the other 2-ODD-C23 isoforms from Arabidopsis or other plants. In contrast to EFE, none of the three Arabidopsis enzymes produced ethylene. Guanidine contents were typically between 10 and 20 nmol*(g fresh weight)-1 in Arabidopsis but increased to 100 or 300 nmol*(g fresh weight)-1 after homoarginine feeding or treatment with Din11-inducing methyljasmonate, respectively. In 2-ODD-C23 triple mutants, the guanidine content was strongly reduced, whereas it increased in overexpression plants. We discuss the implications of the finding of widespread guanidine-producing enzymes in photosynthetic eukaryotes as a so far underestimated branch of the bio-geochemical nitrogen cycle and propose possible functions of natural guanidine production.

    1. Biochemistry and Chemical Biology
    2. Medicine
    Giulia Leanza, Francesca Cannata ... Nicola Napoli
    Research Article

    Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156–0.366]) vs non-diabetic subjects 0.352% [0.269–0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46–30.10] vs non-diabetic subjects 76.24 MPa [26.81–132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=–0.7500, p=0.0255; r=–0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young’s modulus was negatively correlated with SOST (r=−0.5675, p=0.0011), AXIN2 (r=−0.5523, p=0.0042), and SFRP5 (r=−0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.