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.
- 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
-
Transmission and spreading of tauopathy in transgenic mouse brainNature Cell Biology 11:909–913.https://doi.org/10.1038/ncb1901
-
Targeting protein aggregation for the treatment of degenerative diseasesNature Reviews Drug Discovery 14:759–780.https://doi.org/10.1038/nrd4593
-
Critical nucleus size for disease-related polyglutamine aggregation is repeat-length dependentNature Structural & Molecular Biology 18:328–336.https://doi.org/10.1038/nsmb.1992
-
Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structureThe Journal of Biological Chemistry 269:24290–24297.
Article and author information
Author details
Publication history
- 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
-
- 4,583
- views
-
- 527
- downloads
-
- 3
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Alzheimer’s Disease: The two shapes of the Tau protein
eLife 7:e38516.
https://doi.org/10.7554/eLife.38516
Further reading
-
- Biochemistry and Chemical Biology
- Plant Biology
Transmembrane signaling by plant receptor kinases (RKs) has long been thought to involve reciprocal trans-phosphorylation of their intracellular kinase domains. The fact that many of these are pseudokinase domains, however, suggests that additional mechanisms must govern RK signaling activation. Non-catalytic signaling mechanisms of protein kinase domains have been described in metazoans, but information is scarce for plants. Recently, a non-catalytic function was reported for the leucine-rich repeat (LRR)-RK subfamily XIIa member EFR (elongation factor Tu receptor) and phosphorylation-dependent conformational changes were proposed to regulate signaling of RKs with non-RD kinase domains. Here, using EFR as a model, we describe a non-catalytic activation mechanism for LRR-RKs with non-RD kinase domains. EFR is an active kinase, but a kinase-dead variant retains the ability to enhance catalytic activity of its co-receptor kinase BAK1/SERK3 (brassinosteroid insensitive 1-associated kinase 1/somatic embryogenesis receptor kinase 3). Applying hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis and designing homology-based intragenic suppressor mutations, we provide evidence that the EFR kinase domain must adopt its active conformation in order to activate BAK1 allosterically, likely by supporting αC-helix positioning in BAK1. Our results suggest a conformational toggle model for signaling, in which BAK1 first phosphorylates EFR in the activation loop to stabilize its active conformation, allowing EFR in turn to allosterically activate BAK1.
-
- Biochemistry and Chemical Biology
- Neuroscience
Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.
