Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B, Vidal R, Garringer HJ, Shi Y, Ikeuchi T, Murayama S, Ghetti B, Hasegawa M, Goedert M, Scheres SH. Novel tau filament fold in corticobasal degeneration. Nature. 2020 Apr;580(7802):283-287. Epub 2020 Feb 12 PubMed.

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  1. These two papers from Fitzpatrick/Petrucelli and Scheres/Goedert represent a major advance toward a holistic structural understanding of the tau fibril conformers that drive distinct neurodegenerative tauopathies (i.e. "strains", which link specific amyloid conformations to defined biological or pathological phenotypes). Like previous work from the aforementioned authors, the technical achievements of the presented manuscripts are unparalleled and deserve universal attention and acclamation. Nevertheless, one is drawn to a disconnect between the structures presented in the two works. Intriguingly, both structures highlight the presence of tau-independent molecules in fibrils purified from corticobasal degeneration (CBD) brain. In the Scheres/Goedert work on three such samples, a non-covalently attached polyanionic cofactor is implicated, whereas the Fitzpatrick/Petrucelli study (n=2) suggests that post-translational ubiquitin moieties are present. While seemingly pedantic, the relative degree of the pursuant claims of the individual papers makes these discrepancies worthy of additional comment. 

    As two separate groups purified the CBD tau fibrils using slightly different protocols, discrepancies in presence (or absence) of cofactors is not particularly surprising in itself. The provocative claim is that of Fitzpatrick/Petrucelli, who suggest that identified ubiquitin moieties are instrumental in specifying conformer identity and thus strain characteristics. For this to be valid, a simple experiment would suffice: Do such fibrils maintain strain identity in the absence of ubiquitin? A variety of simple cell culture systems have been developed to test this hypothesis and are available to the experimenters. I note this not to be combative, but rather out of deep interest for learning whether non-tau cofactors contribute to strain identity. With strong claims come great interest, and such claims require great evidence.

    View all comments by David Sanders

  2. Arakhamia et al. hypothesize that pronase treatment removes PTMs from the ordered cores of tau filaments, which would lead to their absence in resulting cryo-EM structures. However, in Fitzpatrick et al., 2017, we compared cryo-EM structures of the ordered cores of AD PHFs and SFs prepared with or without pronase. Pronase removed the disordered "fuzzy coat" of the filaments, but did not change the cryo-EM structures of the ordered filament cores. Importantly, this included the additional densities on the outside of the filament cores, hypothesized by Arakhamia et al. to correspond to PTMs.

    Moreover, the cryo-EM structures of tau filaments from a case of PiD (Falcon et al., 2018) were prepared with pronase, whereas pronase was not used in the preparation of tau filaments from the three additional cases of AD in Falcon et al., 2018, from the three cases of CTE in Falcon et al., 2019, or from the three cases of CBD in Zhang et al., mentioned above. Yet, all of these structures show similar additional densities on the outside of the filament cores. These results indicate that pronase treatment does not alter the cryo-EM structures of tau filament cores. 

    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.

    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.

    Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SH, Goedert M. Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Acta Neuropathol. 2018 Nov;136(5):699-708. Epub 2018 Oct 1 PubMed.

    Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R, Crowther RA, Newell KL, Ghetti B, Goedert M, Scheres SH. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. 2019 Apr;568(7752):420-423. Epub 2019 Mar 20 PubMed.

    View all comments by Benjamin Ryskeldi-Falcon

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  1. CryoEM of CBD Tau Suggests Another Unique Protofibril