Freer R, Sormanni P, Vecchi G, Ciryam P, Dobson CM, Vendruscolo M. A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer's disease. Sci Adv. 2016 Aug;2(8):e1600947. Epub 2016 Aug 10 PubMed.

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  1. I think this is a really interesting advance. The biology underlying the specific hierarchical vulnerability patterns has been a mystery for years, and this work has the promise of providing a framework to understand it better. While clearly the patterns of connections play some role, it has always been obvious that specific populations of neurons have a certain predilection toward neurodegeneration in different neurological diseases, likely either superimposed on constraints placed by connectivity, or perhaps even in some ways coordinated with it. This is a “must read” for everyone interested in the balance between protein homeostasis and protein aggregation biology in neurodegenerative syndromes.

    View all comments by Bradley Hyman

  2. This seems like a good systems biology approach to understanding regional vulnerability in protein-aggregating neurodegenerative diseases. The “promoters” and “protectors” selected for this initial analysis are a relatively small series, and no doubt will be supplemented by others as we learn more about the underlying mechanisms that drive aggregation.

    The current reliance only on Braak staging of regional areas might also be enhanced in future work by consideration of in-vivo molecular imaging with Aβ and tau PET studies, which are probably more informative than the classic histological approaches.

    Nevertheless, the identification of a neuronal protein homeostasis signature points strongly to an innate selective vulnerability of certain brain areas, which takes us back to one of the very first neuropathological concepts of “pathoclisis.”

    View all comments by Colin Masters

  3. Freer and collaborators’ findings are very interesting indeed. The notion that there are differences between brain regions regarding their “permissiveness” to protein misfolding disease has been discussed for decades, but strong supporting data have been lacking. Notably, this study highlights the possibility that there exist region-specific differences both in the levels of proteins that promote or protect against protein aggregation, as well as in the levels of proteins engaged in immune system signaling.

    Taken together, the authors suggest that this makes certain brain regions more or less vulnerable to protein misfolding diseases. It is important to stress that the region-specific differences were observed in postmortem brains from normal subjects, and that there is no evidence that levels of “promotors” or “protectors” in a given individual reveal anything about whether he/she is more or less likely to develop disease.

    Further, the authors agree that the findings tell us little about perhaps the most burning issue, namely what the triggers of the diseases are. Importantly, the novel findings remain consistent with the notion that protein aggregates can spread along neural pathways in a prion-like fashion.

    Essentially, the findings imply that some regions are more susceptible to developing neuropathology once proteopathic seeds are delivered from other brain areas, and that the same regions might be less effective at clearing aggregates via the immune system. Future studies might help clarify why these region-specific differences have evolved, and how they are coupled to differences in the normal functions of the different brain regions.

    View all comments by Patrik Brundin

  4. This is an innovative work, which, at least in part, explains the region-specific vulnerability of brain to neurodegenerative processes. The presented scheme is beautiful. I do however have a concern. Systems biology relies on the presumption that all the molecular cause-and-effect relationships described thus far are essentially correct, but this may not always be true. For instance, we still do not know whether phosphorylation is a cause or consequence of tauopathy, questioning the role of GSK3 in AD pathogenesis.

    View all comments by Takaomi Saido

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