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Kim C, Haldiman T, Kang SG, Hromadkova L, Han ZZ, Chen W, Lissemore F, Lerner A, de Silva R, Cohen ML, Westaway D, Safar JG. Distinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer's disease. Sci Transl Med. 2022 Jan 5;14(626):eabg0253. PubMed.
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MRC Laboratory of Molecular Biology
MRC Laboratory of Molecular Biology
What is a conformer?
In chemistry, conformers, or conformational isomers, are sets of molecules having the same bond connectivity sequences that can interconvert by rotation around one or more (sigma) bonds. However, in biology, and in particular the prion field, “conformer” has acquired a narrower meaning. In this context, the word represents a misfolded conformation of an aggregated protein that provides the template for other copies of that protein to misfold and become part of the aggregate, leading to spreading of the misfolded protein (Prusiner, 1998). Misfolding of the prion protein leads to the formation of amyloids, which are helical aggregates with a characteristic cross-β quaternary structure. Different conformers, or prion strains, can spread independently, and have been associated with distinct diseases.
In recent years, it has become clear that other amyloids, such as assembled tau, Aβ, α-synuclein and TDP-43, can also spread through the brain in a prion-like manner. Solid-state NMR, and in particular cryo-EM, have recently obtained a wealth of structural data on amyloid filaments, including those extracted from diseased tissues (Tycko, 2000; Scheres et al., 2020). Amyloids have an ordered core, containing β-sheets that stretch along the direction of the helical axis. In addition, they have a so-called fuzzy coat, where amino acids beyond the N- and C-terminal borders of the ordered core are less structured, i.e., they can adopt a wide range of different conformations. Although the molecular mechanisms of templated seeding are not fully understood, it is assumed that the ordered cores of amyloids provide the conformations for templated seeding of new proteins. Therefore, it is most likely that the structures of the ordered cores of amyloids define conformers.
Kim et al. argue that there are “distinct populations of tau conformers” in their sarkosyl-insoluble preparations of assembled tau from Alzheimer’s disease brains. (The paper's title mentions rapidly progressing sporadic AD, but similar data is presented for less rapidly progressing disease.) These claims are based on indirect measurements of conformation, involving conformation-dependent immunoassays and conformational stability assays. However, decades-old negative-stain EM reports, as well as more recent cryo-EM studies, of sarkosyl-insoluble fractions from AD brain, have failed to provide evidence for the presence of clouds of distinct conformations in tau filament cores. Only two types of AD filaments, with a common protofilament fold, have consistently been identified: paired helical and straight filaments (Crowther, 1991; Fitzpatrick et al., 2017). The same is true of cases of primary age-related tauopathy, with short intervals between memory impairment and death (Shi et al., 2021).
We therefore wonder whether the observations that have led Kim et al. to conclude that there are distinct populations of tau conformers in their samples could be due to effects that originated in the fuzzy coat of the aggregates, rather than in distinct conformations of their ordered cores. We would therefore discourage use of the term “distinct conformers” to describe these entities. Although they would, strictly speaking, still be distinct conformers in the wider meaning of the word in chemistry, this is likely not so in the context of prion-like spreading.
Possibly related to this, we note that the K18/K19 tau constructs that are used in the seeding experiments described by Kim et al. cannot faithfully replicate the AD seed structures, since they lack eight C-terminal residues from the ordered core of AD filaments.
References:
Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83. PubMed.
Tycko R. Solid-state NMR as a probe of amyloid fibril structure. Curr Opin Chem Biol. 2000 Oct;4(5):500-6. PubMed.
Scheres SH, Zhang W, Falcon B, Goedert M. Cryo-EM structures of tau filaments. Curr Opin Struct Biol. 2020 Oct;64:17-25. Epub 2020 Jun 27 PubMed.
Crowther RA. Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2288-92. PubMed.
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.
Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, Newell KL, Vidal R, Garringer HJ, Sahara N, Higuchi M, Ghetti B, Jang MK, Scheres SH, Goedert M. Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607. Acta Neuropathol. 2021 May;141(5):697-708. Epub 2021 Mar 16 PubMed. Correction.
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