Shi Y, Zhang W, Yang Y, Murzin AG, Falcon B, Kotecha A, van Beers M, Tarutani A, Kametani F, Garringer HJ, Vidal R, Hallinan GI, Lashley T, Saito Y, Murayama S, Yoshida M, Tanaka H, Kakita A, Ikeuchi T, Robinson AC, Mann DM, Kovacs GG, Revesz T, Ghetti B, Hasegawa M, Goedert M, Scheres SH. Structure-based classification of tauopathies. Nature. 2021 Oct;598(7880):359-363. Epub 2021 Sep 29 PubMed.

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  1. Tauopathy is present in at least 25 neurodegenerative diseases (Spillantini and Goedert, 2013), and thus it is one of the most common proteopathies to afflict the nervous system. Postmortem investigations of tauopathies have documented the diversity of structure, cellular vulnerability, anatomical distribution, and chemical makeup of the associated lesions. Recent analyses have delved ever more deeply into the molecular underpinnings of disease variability. These cryo-electron microscopic studies present new evidence for a link between the molecular conformation of the tau protein and the resulting clinicopathologic phenotype. The results highlight the diversity of tau structures, while also showing that tauopathies can be hierarchically classified based on the folds adopted by the protein.

    Some thoughts on this intriguing investigation:

    1. The findings reinforce the conclusion that, although tauopathy is a frequent neurodegenerative phenomenon, it is by no means a unitary disorder clinically, histopathologically, or molecularly. Some causes of variation are coming to light, but many uncertainties remain. Among these, the differential involvement of glial cells and neurons in these various tauopathies is a critical open question.
    2. Exactly how Aβ-proteopathy leads to tauopathy in AD remains unknown. It is interesting that, in familial British dementia, familial Danish dementia, and prion diseases with PrP-amyloid, the tau fold resembles that in AD. For example, the amyloid in familial British dementia consists of a protein that results from a defective stop codon; translation of the elongated open reading frame, and processing of the precursor generates a protein segment with no known function, and yet it, like misfolded Aβ, is highly amyloidogenic (Vidal et al., 1999). Hence, amyloid deposition (“amyloid” in the true, generic sense; Walker, 2020) yields a particular pathologic strain of tau. What common feature of amyloid is responsible for the “AD fold” of tau? Are oligomers involved (Cantlon et al., 2015)? It is also noteworthy that amyloid per se is not essential for driving this particular fold, as it is found in primary age-related tauopathy (PART).
    3. While the different tau folds in different diseases suggest the emergence and spread of disease-specific seeds within the brain, this hypothesis should be tested in experimental animals, the caveat being that truly human-like tauopathy remains elusive in genetically modified rodents. As the authors suggest, cryo-EM studies of experimental animals could inform the translational utility of these models.
    4. This investigation includes a respectable number of subjects for such technically challenging experiments, but future studies should expand the number of both subjects and brain areas examined. A balanced analysis of males and females is required to rule out the possibility of sex differences in the susceptibility to different tau strains. Also, does the stage of disease development influence the molecular phenotype of tau, i.e., do the characteristics of the folds and/or the cell types involved change over time?

    Once again, cryo-EM is showing its value in illuminating the nature of pathogenic proteins. In his seminal presentation in 1906 (Alzheimer, 1907), Alois Alzheimer argued that histopathologic analysis would yield a more precise definition of neurologic diseases than can be gleaned from clinical assessment alone. By defining the molecular configuration of tau polymers derived from multiple tauopathies, Shi and colleagues take Alzheimer's argument a step further: from histopathology to molecular proteopathy.

    To loosely paraphrase Alzheimer, cryo-EM is revealing more molecular subtypes of tauopathy than are currently recognized by our textbooks. That said, these seemingly disparate disorders are united by a common thread, which also happens to define numerous other brain diseases. It is that the key to a great many neurodegenerative disorders lies in the problem of altered protein structure.

    References:

    Cantlon A, Frigerio CS, Freir DB, Boland B, Jin M, Walsh DM. The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers. J Biol Chem. 2015 Jul 3;290(27):16502-16. Epub 2015 May 8 PubMed.

    Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol. 2013 Jun;12(6):609-22. PubMed.

    Vidal R, Frangione B, Rostagno A, Mead S, Révész T, Plant G, Ghiso J. A stop-codon mutation in the BRI gene associated with familial British dementia. Nature. 1999 Jun 24;399(6738):776-81. PubMed.

    Walker LC. Aβ Plaques. Free Neuropathol. 2020;1 Epub 2020 Oct 30 PubMed.

    View all comments by Lary Walker

  2. This is a really important paper. It brings clarity and insight into what had begun to seem an ever-more-complex taxonomy of tauopathies since cryo-EM augmented the isoform and clinical classifications. The new hierarchical dendrogram that classifies and subtypes the family of tauopathies according to microstructure folds is not only commended for its inclusion of both common and rare tauopathies, but also for providing a principled way to predict and confirm new tauopathies. It will help the design and stratification of new anti-tau therapeutics.

    View all comments by James Rowe

  3. In my opinion this is an important, paradigm-shifting paper. It reports for the first time the cryo-EM-derived structure of tau filaments in PSP, the prototypical primary tauopathy, and in a variety of other tau-related disorders.

    Building on previous work from Goedert’s and Scheres' labs (in AD, CTE, CBD, and Pick’s), we now have a broad view of similarities and differences in the structure of aggregates across a broad range of tauopathies.

    The novel classification scheme proposed here provides a roadmap for future study of tauopathies that is grounded in structural biology and has significant implications for biomarker and drug development. For example, the fact that aggregates in PSP and CBD, previously considered collectively as “4R tauopathies,” have different folding structures suggests that the fibrils in these disorders may interact very differently with small molecules that are being developed as PET tracers or therapeutics.

    The heterogeneity of tauopathies may be even greater than we previously imagined, which is a bit daunting but also incredibly informative for future work.

    View all comments by Gil Rabinovici

  4. This paper represents an important milestone in shifting the definition of sub-entities within the group of tauopathies from syndrome-based, biochemical, or neuropathology-based classification systems to structural biophysical principles.

    This novel approach does not refute the previous classifications, nor does it deprive them of their justification. In a multidimensional classification, the earlier principles remain valid and useful, e.g., for clinical diagnosis and symptomatic therapies, neuropathological diagnosis, and neurobiological studies on the relative contribution of different cell types.

    However, the new biophysical classification seems to provide the stratification that is most upstream within the neurobiology of tauopathies so far. This can open new avenues for the development of diagnostic and therapeutic instruments.

    Whether the suggested tau folds observed in the intracellular aggregates are identical to the spreading or toxic tau samples, i.e., the targets for therapy, remains to be shown.

    View all comments by Günter Höglinger

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