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Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI. Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4376-85. Epub 2014 Sep 26 PubMed.
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Institute of Neurology
Marc Diamond and colleagues at Wash U have produced a very exciting paper underlining the similar “prion-like” mechanisms of common neurodegenerative diseases. The authors have developed an excellent, sensitive assay system for looking at tau seeding in human and mouse tissues. They find clear seeding activity long before any detectable histopathological changes and this is exactly what was shown early this year by John Collinge’s group for the prion protein: Neuropathology only occurs sometime after reaching a particular titre of the misfolded protein (Sandberg et al., 2014). As it happens, David Borchelt’s group has just published the first animal-to-animal transmission of SOD1 pathology, which causes another neurodegenerative disease, amyotrophic lateral sclerosis, and so we can see that evidence for common prion-like mechanisms in neurodegenerative disease is robust and clear (Ayers et al., 2014). This has exciting implications for potentially developing related therapeutic strategies for these diseases.
This work, using a FRET-based assay that amplifies the signal from conformationally misfolded proteins, continues a strong series of studies from the Diamond lab examining the cell biology of misfolded tau and its ability to cross cell membranes. Especially interesting here is the development of an assay—and its general applicability—that demonstrates ultrasensitive detection of such misfolded proteins. While a full appreciation will come over time for how this information fits into more traditional approaches (dating back to silver stains that—conceptually at least—detect and visualize abnormally folded proteins), the work presented here shows nicely that the new approach detects changes sooner than previous technologies, and now gives us tools to begin to explore the consequences of those early changes. This is a “must read” paper.
This is an absolutely important paper on the development of an assay that detects tau seeding activity using a combination of FRET flow cytometry and a tau monoclonal FRET biosensor line. By combining the techniques the authors demonstrated they can detect seeds in the femtomolar range. Using brain homogenates from AD patients and people with other neurodegenerative diseases, they confirmed a high specificity of the seeding reaction, since tau seeding activity was detected in AD brains only. Tau seeding activity increased with age in a mouse model of tauopathy. Moreover, tau seeding activity was the earliest marker of disease pathology in the model. Taken together, these results add an important piece of the puzzle of the role of tau in neurodegenerative disorders and open a new direction toward the development of potentially a very early, preclinical diagnostic tool.
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