On 2017 Mar 07, Claudiu Bandea commented:

Are the conclusions of the Lancet Neurology article by Stopschinski and Diamond flawed?

In their article entitled “The prion model for progression and diversity of neurodegenerative diseases”(1), Barbara Stopschinski and Marc Diamond conclude: “We do not know if common neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, ALS and Huntington's disease) involve transcellular propagation of protein aggregation, as predicted by the prion model. Until specific interventions are able to block protein propagation and successfully treat patients, this model will be mainly speculative” (italics and parenthesis added).

Given that one of the authors, Marc Diamond, published several previous articles in which he refers to the primary proteins implicated in neurodegenerative diseases as 'prions' [see for example: “Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo” (2) and “Propagation of prions causing synucleinopathies in cultured cells” (3)], it is surprising to learn in this new article (1) that, in fact, we do not know if these neurodegenerative disorders are caused by 'prions'. Does this mean that there are no “Tau Prion Strains” and there are no “Propagation of prions causing synucleinopathies”?

Also, how do the authors reconcile their conclusion with the following statement in the Abstract of a concurrently published paper entitled “Cellular Models for the Study of Prions”(4): “It is now established that numerous amyloid proteins associated with neurodegenerative diseases, including tau and α-synuclein, have essential characteristics of prions, including the ability to create transmissible cellular pathology in vivo”?

Further, Stopschinski and Diamond state that “until specific interventions are able to block protein propagation and successfully treat patients” the prion model remains speculative. If that’s the case, have these “specific interventions” (which would prove that Alzheimer's, Parkinson's, ALS and Huntington's are indeed caused by ‘prions') been used to also validate that the disorders traditionally defined as ‘prion diseases’, such as Creutzfeld-Jakob disease, are indeed caused by 'prions'? If not, is the prion model for Creutzfeld-Jakob disease just speculative?

In their outline of future directions, the authors write: “Given the wide ranging role of self-replicating protein aggregates in biology, we propose that pathological aggregation might in fact represent a dysregulated, but physiological function of some proteins—ie, the ability to change conformation, self-assemble, and propagate” (1).

This is a remarkable statement in that it points to the radical idea that the pathological aggregation of the proteins implicated in neurodegenerative diseases, such as tau, amyloid β, α-synuclein and ‘prion protein’, is an intrinsic phenomenon associated with their physiological function, which is a profound departure from the conventional view presented in thousands of publications over the last few decades. However, I have a problem with the formulation of the statement, specifically with “…we propose…”. The authors might not be fully familiar with the literature on neurodegenerative diseases, but what they are proposing has been the primary topic of articles published several years ago (e.g. 5, 6).

Given the extraordinary medical, public health and economic burden associated with neurodegenerative diseases, it should be expected for the authors or the editorial team/reviewers (7) to address the questions and issues posted in this comment.

References

(1) Stopschinski BE, Diamond MI. 2017. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurology. doi: 10.1016/S1474-4422(17)30037-6. Stopschinski BE, 2017

(2) Kaufman SK, Sanders DW, Thomas TL et al. 2016. Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron. 92(4):796-812. Kaufman SK, 2016

(3) Woerman AL, Stöhr J, Aoyagi A, et al. 2015. Propagation of prions causing synucleinopathies in cultured cells. Proc Natl Acad Sci U S A. 112(35):E4949-58. Woerman AL, 2015

(4) Holmes BB, Diamond MI. 2017. Cellular Models for the Study of Prions.Cold Spring Harb Perspect Med. doi: 10.1101/cshperspect.a024026. Holmes BB, 2017

(5) Bandea CI. 2009. Endogenous viral etiology of prion diseases. Nature Precedings. http://precedings.nature.com/documents/3887/version/1/files/npre20093887-1.pdf

(6) Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi:10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

(7) George S, Brundin P. 2017. Solving the conundrum of insoluble protein aggregates. Lancet Neurol. doi: 10.1016/S1474-4422(17)30045-5. George S, 2017

On 2017 Mar 07, Claudiu Bandea commented:

Are the conclusions of the Lancet Neurology article by Stopschinski and Diamond flawed?

In their article entitled “The prion model for progression and diversity of neurodegenerative diseases”(1), Barbara Stopschinski and Marc Diamond conclude: “We do not know if common neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, ALS and Huntington's disease) involve transcellular propagation of protein aggregation, as predicted by the prion model. Until specific interventions are able to block protein propagation and successfully treat patients, this model will be mainly speculative” (italics and parenthesis added).

Given that one of the authors, Marc Diamond, published several previous articles in which he refers to the primary proteins implicated in neurodegenerative diseases as 'prions' [see for example: “Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo” (2) and “Propagation of prions causing synucleinopathies in cultured cells” (3)], it is surprising to learn in this new article (1) that, in fact, we do not know if these neurodegenerative disorders are caused by 'prions'. Does this mean that there are no “Tau Prion Strains” and there are no “Propagation of prions causing synucleinopathies”?

Also, how do the authors reconcile their conclusion with the following statement in the Abstract of a concurrently published paper entitled “Cellular Models for the Study of Prions”(4): “It is now established that numerous amyloid proteins associated with neurodegenerative diseases, including tau and α-synuclein, have essential characteristics of prions, including the ability to create transmissible cellular pathology in vivo”?

Further, Stopschinski and Diamond state that “until specific interventions are able to block protein propagation and successfully treat patients” the prion model remains speculative. If that’s the case, have these “specific interventions” (which would prove that Alzheimer's, Parkinson's, ALS and Huntington's are indeed caused by ‘prions') been used to also validate that the disorders traditionally defined as ‘prion diseases’, such as Creutzfeld-Jakob disease, are indeed caused by 'prions'? If not, is the prion model for Creutzfeld-Jakob disease just speculative?

In their outline of future directions, the authors write: “Given the wide ranging role of self-replicating protein aggregates in biology, we propose that pathological aggregation might in fact represent a dysregulated, but physiological function of some proteins—ie, the ability to change conformation, self-assemble, and propagate” (1).

This is a remarkable statement in that it points to the radical idea that the pathological aggregation of the proteins implicated in neurodegenerative diseases, such as tau, amyloid β, α-synuclein and ‘prion protein’, is an intrinsic phenomenon associated with their physiological function, which is a profound departure from the conventional view presented in thousands of publications over the last few decades. However, I have a problem with the formulation of the statement, specifically with “…we propose…”. The authors might not be fully familiar with the literature on neurodegenerative diseases, but what they are proposing has been the primary topic of articles published several years ago (e.g. 5, 6).

Given the extraordinary medical, public health and economic burden associated with neurodegenerative diseases, it should be expected for the authors or the editorial team/reviewers (7) to address the questions and issues posted in this comment.

References

(1) Stopschinski BE, Diamond MI. 2017. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurology. doi: 10.1016/S1474-4422(17)30037-6. Stopschinski BE, 2017

(2) Kaufman SK, Sanders DW, Thomas TL et al. 2016. Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron. 92(4):796-812. Kaufman SK, 2016

(3) Woerman AL, Stöhr J, Aoyagi A, et al. 2015. Propagation of prions causing synucleinopathies in cultured cells. Proc Natl Acad Sci U S A. 112(35):E4949-58. Woerman AL, 2015

(4) Holmes BB, Diamond MI. 2017. Cellular Models for the Study of Prions.Cold Spring Harb Perspect Med. doi: 10.1101/cshperspect.a024026. Holmes BB, 2017

(5) Bandea CI. 2009. Endogenous viral etiology of prion diseases. Nature Precedings. http://precedings.nature.com/documents/3887/version/1/files/npre20093887-1.pdf

(6) Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi:10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

(7) George S, Brundin P. 2017. Solving the conundrum of insoluble protein aggregates. Lancet Neurol. doi: 10.1016/S1474-4422(17)30045-5. George S, 2017