Walsh DM, Selkoe DJ.
A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration.
Nat Rev Neurosci. 2016 Apr;17(4):251-60.
PubMed.
Mathias Jucker Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE Tübingen
Posted:
The possibility is raised that the spread of protein aggregates can easily be explained by the idea that cells under stress begin to form protein aggregates and thus protein aggregation can be initiated along "stressed" neural networks rather than by the spread of the protein seeds themselves.
This possibility is very well taken and thus it is important to control for it!
However, it is important to note that, in the seeding paradigm, prions beget prions in recipient cells, tau seeds beget tauopathy, and synuclein seeds beget synucleinopathy. Furthermore, in many studies two different seeds (strains) of the same protein have been used to test the two alternatives. The observation that a seed with conformation A leads to the induction and spreading of conformation A while a seed with conformation B leads to the induction and spreading of conformation B is somewhat difficult to reconcile with the idea that the spreading of aggregation is the result of neural stress, which would be expected to have relatively nonspecific effects on downstream targets.
This is a well-reasoned analysis of the protein-spread hypothesis that should be studied by every AD investigator. Some important take-away messages:
“The molecular mechanisms of PrP proliferation and neurotoxicity in ‘classical’ prion diseases are not fully understood and therefore referring to a pathogenic process as prion-like does not provide mechanistic precision.”
“The Braak staging system is neither proof of, nor an argument against, the spreading hypothesis.”
“Need to link the progressive development of histological lesions to actual functional effects. Longitudinal studies in transgenic mice suggest that the existence of neurofibrillary tangles per se may not necessarily disrupt neural function.”
“It should be emphasized that, even after more than 30 years of intensive investigation, the sites of conversion of cellular PrP into infectious and neurotoxic forms of PrP are unknown.”
“Moreover, there remains an urgent need to identify the actual neurotoxic agents in both prion diseases and non-PrP neurodegenerative diseases. This point cannot be overstated.”
This certainly is an important and thoughtful commentary that keeps us focused on unanswered questions. However, I would take issue with the statement that “the molecular mechanisms of PrP proliferation and neurotoxicity in ‘classical’ prion diseases are not fully understood and therefore referring to a pathogenic process as prion-like does not provide mechanistic precision.” Certainly there are gaps in our knowledge, particularly with regard to cell biological mechanisms (when are there not?). But the literature on PrP-prion diseases is long and deep, and the basic molecular features that define prions – even in their variability - are sufficiently well established to give heuristic power to the prion paradigm as it applies to other neurodegenerative diseases.
Comments
Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE Tübingen
The possibility is raised that the spread of protein aggregates can easily be explained by the idea that cells under stress begin to form protein aggregates and thus protein aggregation can be initiated along "stressed" neural networks rather than by the spread of the protein seeds themselves.
This possibility is very well taken and thus it is important to control for it!
However, it is important to note that, in the seeding paradigm, prions beget prions in recipient cells, tau seeds beget tauopathy, and synuclein seeds beget synucleinopathy. Furthermore, in many studies two different seeds (strains) of the same protein have been used to test the two alternatives. The observation that a seed with conformation A leads to the induction and spreading of conformation A while a seed with conformation B leads to the induction and spreading of conformation B is somewhat difficult to reconcile with the idea that the spreading of aggregation is the result of neural stress, which would be expected to have relatively nonspecific effects on downstream targets.
Yale University School of Medicine
This is a well-reasoned analysis of the protein-spread hypothesis that should be studied by every AD investigator. Some important take-away messages:
Emory University
This certainly is an important and thoughtful commentary that keeps us focused on unanswered questions. However, I would take issue with the statement that “the molecular mechanisms of PrP proliferation and neurotoxicity in ‘classical’ prion diseases are not fully understood and therefore referring to a pathogenic process as prion-like does not provide mechanistic precision.” Certainly there are gaps in our knowledge, particularly with regard to cell biological mechanisms (when are there not?). But the literature on PrP-prion diseases is long and deep, and the basic molecular features that define prions – even in their variability - are sufficiently well established to give heuristic power to the prion paradigm as it applies to other neurodegenerative diseases.
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