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Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SH, Goedert M. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018 Sep;561(7721):137-140. Epub 2018 Aug 29 PubMed.
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Emory University
Cryo-electron microscopy (cryo-EM, aka electron cryomicroscopy) has become the go-to tool for determining the molecular architecture of alternatively folded proteins in various disease states. A particular advantage of cryo-EM is that it can be applied to individual protein polymers taken directly from the brain, and thus yield a reconstruction of the protein's molecular shape as it existed in real life. Falcon and colleagues previously exploited this capability to ascertain the structure of the ordered core of tau protein in Alzheimer's disease (Fitzpatrick et al., 2017). Now they show that polymerized tau in Pick's disease, which (unlike in AD) consists only of the three-repeat isoform of tau, adopts a disease-specific fold (called the “Pick fold”). The brain-derived, Pick-folded tau is able to seed the self-assembly of recombinant 3R- but not 4R-tau, explaining why only 3R-tau is present in Pick bodies even though humans express approximately equal amounts of both isoforms.
By showing that tau filaments in Pick’s disease differ from those in Alzheimer's disease, these intriguing findings provide direct evidence that tau adopts different three-dimensional architectures, or proteopathic strains, in different diseases. Function follows form, then, in pathobiology as in normobiology, but the next step is to determine exactly how molecular architecture is linked to the different types of disease caused by a given protein. It will be important to fit oligomeric assemblies into the puzzle—for example, is the molecular architecture of fibrils related in some way to the formation, structure, and/or pathogenicity of oligomers? And finally, how can detailed structural information guide therapeutic strategies? This cryo-EM analysis by Falcon and co-workers, and the many that certainly will follow, should help to resolve important questions about how aberrant proteins cause disease.
—David Lynn at Emory is the co-author of this comment.
References:
Fitzpatrick AW, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SH. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. Epub 2017 Jul 5 PubMed.
View all comments by Lary WalkerNIH/NIAID Rocky Mountain Laboratories
The recent structures from Goedert and colleagues are quite illuminating and have far-reaching implications. The fact that tau filaments of Pick’s and Alzheimer’s diseases have distinct amyloid core folds implies that they will likely have different chemical surfaces, tendencies to interact with other factors and tissue components, preferred sites of accumulation, cytotoxicities, and thereby, neuropathological and clinical consequences. The results also provide a structural basis for the profound amyloid seeding/templating selectivity that we have observed for Pick’s disease tau aggregates in our ultrasensitive 3R tau RT-QuIC assay (Saijo et al., 2017). The distinct seeding templates presented by Pick’s and AD tau filaments presumably underpins the faithful prion strain-like propagation of these pathological conformers of tau amyloids.
References:
Saijo E, Ghetti B, Zanusso G, Oblak A, Furman JL, Diamond MI, Kraus A, Caughey B. Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid. Acta Neuropathol. 2017 May;133(5):751-765. Epub 2017 Mar 14 PubMed.
View all comments by Byron CaugheyUniversity of California, San Diego
Benjamin Falcon’s recent paper describing the crystal structure of three-repeat tau isolated from the brains of Pick’s disease patients is remarkable for the fact that we can now see how the two major isoforms of tau protein fold in distinctly different ways. T-tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the gene MAPT. Alternative splicing can generate six different isoforms that can be distinguished based on the presence of zero, 1, or 2 N-terminal inserts and the presence or absence of repeat domain 2 (3R or 4R). These three-repeat (3R) or four-repeat (4R) tau species are differentially expressed in neurodegenerative diseases with progressive supranuclear palsy and Alzheimer’s disease primarily expressing the 4R tau isoform while Pick’s disease and behavior variant frontotemporal dementia (bvFTD) primarily express the 3R tau isoform (Ginsberg et al., 2006).
This recent finding shows by cryo-electron microscopy the difference in folding between the 3R tau and the 3R/4R tau. Although the 3R and 4R tau proteins are found in equal molar concentrations in healthy neurons, the 4R tau preferentially accumulates in Alzheimer’s disease, and the 3R tau preferentially accumulates in Pick’s disease and some forms of FTD. To date, most approaches to tau immunotherapy have focused on total tau or the 4R tau protein. This study shows us how the two isoforms significantly differ in their folding in the pathogenic state. It will be interesting to see if the 3R tau and 4R tau proteins in the healthy brain retain the same folding structures as observed in this study.
Among the many functions attributed to tau protein in axons, directing axonal transport has been the subject of recent interest with respect to tau pathology. Anterograde and retrograde transport of cargo in the axon are mediated by the kinesin and dynein motors interacting with microtubules. Tau regulates axon transport directionality by interacting with microtubules and competing for binding of these cargo transport motors. Recently, Lacovich et al. reported that the ratio of 3R tau and 4R tau in the axon can direct the transport of cargo, with higher levels of 3R tau favoring anterograde transport toward the cell body and inhibiting the retrograde transport of those same cargos (Lacovich et al., 2017). Thus, the differences in folding of the C-terminus of the protein of 3R tau and 4R tau may play a role in the directionality of cargo transport.
Another interesting finding from this study was differences in exposure of the traditional serine 262 phosphorylation site often used as a marker of tau accumulation. Falcon et al. show with the cryo-EM structure of 3R tau that that Serine262 is hidden inside the β-sheet core whereas with 4R tau this residue is assessable for phosphorylation. This may explain the differential phosphorylation of these two tau species.
References:
Ginsberg SD, Che S, Counts SE, Mufson EJ. Shift in the ratio of three-repeat tau and four-repeat tau mRNAs in individual cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease. J Neurochem. 2006 Mar;96(5):1401-8. PubMed.
Lacovich V, Espindola SL, Alloatti M, Pozo Devoto V, Cromberg LE, Čarná ME, Forte G, Gallo JM, Bruno L, Stokin GB, Avale ME, Falzone TL. Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons. J Neurosci. 2017 Jan 4;37(1):58-69. PubMed.
View all comments by Brian SpencerIndiana University School of Medicine
The recent structural studies illuminate that Pick’s disease is picky in selecting a repeat to fold into tau aggregates.
Falcon and colleagues have demonstrated an exciting difference at the molecular level between Alzheimer’s disease and Pick’s disease (PiD). The finding is an excellent use of cryo-EM, but it was not only cryo-EM. High-quality “classic” neuropathology dissection was necessary, and this was followed up by biochemical filament extraction and crystallization before cryo-EM could generate a model for the (now known to be) PiD-unique “J” structure of tau aggregates. Western blotting determined the absence of the anti-R2 antibody target and confirmed that the structure was exclusively made up of “a novel fold of 3R tau” (Falcon et al., 2018). This is in striking contrast to the aggregates of AD, which include both 3R and 4R tau. However, the striking element of the report is that tau filaments from the Pick’s disease patient’s brain would only seed aggregation of full-length 3R tau into the Pick “J” form, without having any effect on 4R, while 3R and 4R AD aggregates could seed both 3R and 4R tau to fold into the AD “C” form. In other words, a distinct molecular pathology feature of Pick’s is propagated through selective structural seeding, without gene transcription, transcription processing, or translation mechanisms intervening.
Modern structural and classical protein biochemistry and neuropathology techniques, among others, have converged elegantly in this work. Its value indeed spreads far beyond structural characterization.
As has been noted, function follows form, and the differences in form may help untangle differences in (dys)function between AD and PiD. Furthermore, by defining a distinct PiD tau subunit structure, Falcon’s group has defined several concrete questions: How does tau end up with that particular structure versus the AD-typical structure? Is the difference determined early in PiD etiology or is there a “general predegenerative condition” that later diverges toward AD versus PiD (versus FTLD, etc.)? How do the PiD versus AD tau aggregate subunits specifically differ in their dysfunctions? Finally, what processes drive a brain to form Pick folds vs. AD folds?
In short, this work’s influence will touch far beyond reporting a structural novelty of tau in PiD versus AD.
References:
Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SH, Goedert M. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018 Sep;561(7721):137-140. Epub 2018 Aug 29 PubMed.
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