. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. 2019 Apr;568(7752):420-423. Epub 2019 Mar 20 PubMed.


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  1. This new report from the MRC Laboratory of Molecular Biology is yet another fascinating look at the molecular heterogeneity of polymeric tau. Tauopathy occurs in more than 20 different brain diseases (Spillantini et al., 2013), and thus may be the most common type of cerebral proteopathy. Even within the subset of tauopathies known as frontotemporal lobar degeneration–tau (FTLD-tau), the disease phenotype is quite variable (Dickson et al., 2011), but the source of variation, including selective regional and cellular vulnerability, remains uncertain.

    Using cryo-electron microscopy (cryo-EM), Falcon and colleagues compared the molecular architecture of tau filaments from subjects who had died either with CTE or AD. This comparison is interesting because the tau that aggregates in the two disorders is similar, i.e., non-mutant tau consisting of all six isoforms of the protein. The researchers discovered that the molecular fold of tau in CTE differs from that in AD just enough to incorporate a mysterious molecular “rod” that runs within the long axis of the filament. This hydrophobic molecular inclusion could be a cofactor that influences the structure and possibly the pathobiology of aberrant tau; the authors speculate that it might consist of molecules such as non-polar sterols or fatty acids, but its true identity has yet to be revealed. In any case, it is apparent from this compelling cryo-EM analysis that polymeric tau in CTE differs structurally from that in AD.

    One implication of the findings is the increasingly probable importance of biological cofactors in governing the structure and function of misfolded proteins in general. It has long been known that assemblies of recombinant or synthetic proteins often lack the seeding potency of the proteins that aggregate within the living organism (Jucker and Walker, 2018), although the in vivo seeding capacity (infectivity) of recombinant prion protein aggregated in vitro can be augmented by the inclusion of specific biomolecules during aggregation (Supattapone, 2014). As Falcon et al. note, identification of the enigmatic molecules incorporated within CTE tau could yield clues to tau's variable pathobiology, and possibly open new paths to diagnosis and treatment. Although the regional distribution of tauopathy in CTE can be explained, at least in part, by the physical effects of head injury on the brain, it is conceivable that the inclusion influences in some way the cellular and regional idiosyncrasies of CTE tauopathy.

    Among the many questions to be addressed are the cause-and-effect relationship between the inclusion and the structure of tau molecules, the effects of the inclusion on the toxicity and seeding capacity of tau, and its impact, if any, on the pathobiology of oligomeric tau. Given the molecular similarity of tau in individuals with CTE and AD, it will be informative to determine why AD filaments lack the rod-like inclusions. And finally, one wonders whether such seemingly anomalous substances might occur in other proteinaceous fibrils.


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    View all comments by Lary Walker
  2. This study clearly shows that CTE tau pathology is different from AD tau pathology and apparently each tauopathy has its own specific tau pathology signatures. I suspect that these different signatures of tau pathology in different tauopathies that show as different morphologies are very likely products of different posttranslational modifications. In 1996, we showed that de-glycosylation of AD neurofibrillary tangles (NFT)/paired-helical filaments converted them into straight filaments (Wang et al., 1996). Most recently, we showed that while AD phospho-tau injected in mouse hippocampus produces AD-like NFTs, AD p-tau partially dephosphorylated by PP2A produces argyrophilic grain-like tau pathology (Hu et al., 2016). Similarly, tau truncated at different sites and different combinations of 3R and 4R tau can produce tau pathology with different morphologies.


    . Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease. Nat Med. 1996 Aug;2(8):871-5. PubMed.

    . Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement. 2016 Oct;12(10):1066-1077. Epub 2016 Apr 28 PubMed.

    View all comments by Khalid Iqbal

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