On 2017 Jan 09, Gerhard Holt commented:

Intimate Cohabitants'Shared Microbiomes and Alpha-Synuclein Pathology

Sampson et al.'s findings on the role of gut microbiota on Alpha-synucleinopathies[1] raise considerable potential concern regarding the microbiome of intimate cohabitants of patients with Alpha-Synuclein pathology, since they are likely to have substantial exposure to a shared microbiome.

Do these intimate cohabitants develop more early Alpha-Synuclein pathology than non-cohabitant controls ?

Are they at greater risk for Parkinson's disease and other alpha-synucleinopathies ?

From an Infectious Disease perspective, this might be an important clinical study.

Perhaps some of the intimate cohabitants are more resistant to A-SYN pathology, SCFAs, or the underlying gut microbes than others - despite similar microbiome exposure ?

Perhaps differences in the interactions between their immune systems and their microbiome alter outcomes ?

This might be a fertile area for differential proteome studies.

Given the importance of Sampson et al.'s findings, hopefully a clinical trial of antibiotics followed by (healthy donor) fecal transplant for patients with Parkinson's Disease will soon follow - perhaps with a cross-over design.

Given the low risks of a potential treatment which uses well known medications and a well established procedure (Fecal Transplant), and given the grossly disproportionate potential benefit, hopefully this study will be expedited in humans.

It may be useful however to also study Alpha-Synuclein pathology in their intimate cohabitants relative to controls.

References :

[1] Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease Sampson, Timothy R. et al. Cell , Volume 167 , Issue 6 , 1469 - 1480.e12

  <www.cell.com/cell/pdf/S0092-8674(16)31590-2.pdf>

On 2016 Dec 20, Claudiu Bandea commented:

The etiology of Parkinson's disease is not an enigma

In a recent expert review article entitled “How close are we to revealing the etiology of Parkinson's disease?” (1), Kurt Jellinger concluded: “Although major advances have been made in our understanding of the etiology (and pathogenesis) of PD (and related synucleinopathies) over the last 20 years, it remains as much an enigma as when James Parkinson first described its clinical features” (italics added).

It remains to be seen if the study by Sampson et al. (2) will join the growing list of “major advances” in the field of Parkinson’s, which have revealed numerous contributing factors, including environmental (e.g. toxins), microbial (e.g. various bacteria and viruses), physiological (e.g. oxidative stress) and genetic (e. g. mutations) in addition to the main risk factor - aging.

But what if the etiology of Parkinson’s has remained an enigma primarily because of these “major advances”? What if, by promoting a multitude of different causes and pathogenic mechanisms, each supported by strong data and observations, these “major advances” have led to confusion and have constrained progress? What if Parkinson’s enigma is a classic case of ‘not seeing the forest because of the trees’?

Contrary to the conventional thinking in the field, I recently proposed that the existing data and observations, including those in Sampson et al. (2) and other “major advances”, when integrated in a comprehensive conceptual framework that makes biological and evolutionary sense, point towards a sensible solution to Parkinson’s enigma (3, 4; for recent additional evidence see Ref. 5):

(i) α-synuclein (aSyn), the primary protein implicated in Parkinson’s and related synucleinopathies, is a member of the innate immune system;

(ii) The assembly of αSyn into various oligomers and fibers is not a protein misfolding event as currently defined, nor is it a prion-like replication/propagation activity, but it is an integral part of its biological function in innate immunity;

(iii) The activities associated with the immune function of αSyn lead to Parkinson’s and other synucleinopathies, which are innate autoimmune disorders.

Sampson et al. (2) performed a series of ingenious experiments evaluating the impact of gut microbiota and some of their metabolites on the aggregation of αSyn, activation of microglia, and motor and gut motility deficits in a transgenic mouse model for Parkinson’s that expresses high levels of human αSyn. Similar to other studies showing a strong influence of enteric microbiota on the immune and nervous systems, the results showed that, compared to germ-free transgenic mice, mice carrying complex gut microbiota had increased αSyn associated pathology and microglia activation in the brain and displayed progressive deficit in motor functions and gut motility. The study would have benefited from parallel experiments in mice with disrupted vagal nerve, likely the main portal for αSyn aggregates (as well as for neurotropic microbial/viral pathogens) to the brain, particularly in the light of the finding that the administration of a mixture of short-chain fatty acids, which can reach the brain via the blood circulatory system, simulates the effects of gut microbiota. Perhaps the most intriguing finding reported by Sampson et al. was that the gut microbiota transferred from patients with Parkinson’s enhanced motor impairments, whereas the microbiota from healthy human donors did not, which suggested that the effects might be induced by specific Parkinson’s associated microbial taxa; however, I suggest an additional putative mechanism: the impairment was initiated by ‘αSyn oligomeric seeds’ that were transferred from the patients with Parkinson’s.

As interesting and valuable the results reported Sampson et al. (2) are, the authors have failed to make sense of them in context of the other “major advances” in the field, thereby adding to the enigma (i.e. confusion) regarding the etiology of Parkinson’s and related synucleinopathies.

For example, given that the ‘prion’ concept has been one of the major emerging paradigms in the field of Parkinson’s and other neurodegenerative diseases, including Alzheimer’s, Huntington’s, and ALS (e.g. 5-10), it is highly surprising that Sampson et al. have only mentioned it in the following statement: “Braak’s hypothesis posits that aberrant αSyn accumulation initiates in the gut and propagates via the vagus nerve to the brain in a prion-like fashion (Del Tredici and Braak, 2008)” (italics added). It appears that “Del Tredici and Braak, 2008” reference is a technical error as it doesn’t present a “Braak’s hypothesis”; possibly, Sampson et al. intended to refer to the ‘dual-hit hypothesis’, first presented in 2007 and re-published by the same authors two years later (11). Nevertheless, as I have previously discussed (3,4,12), the ‘prion hypothesis’ is probably flawed, so I commend Sampson et al. for omitting it, but I doubt that the authors were motivated by the same perspective.

I end this brief essay on Sampson et al. (2) by outlining its major weakness, which it is shared with most studies addressing the role of αSyn: the failure to consider the physiological function of αSyn when exploring its pathogenic mechanisms and the etiology of Parkinson’s and related synucleinopathies. Unfortunately, the prion hypothesis and the associated ‘protein misfolding’ paradigm have conceptually uncoupled the pathogenic mechanisms associated with αSyn, as well as with the other main proteins implicated in neurodegeneration (e.g. APP/amyloid-β, tau, huntingtin, TDP-43, prion protein), from their evolutionarily selected biological function (3,4). As recently suggested, the paths toward understanding neurodegeneration must be re-evaluated (13), and this should start with assessing the scientific foundation of the prion hypothesis and protein misfolding paradigm, which are questionable.

References:

(1) Jellinger KA. 2015. How close are we to revealing the etiology of Parkinson's disease? Expert Rev Neurother. 15(10):1105-7. Jellinger KA, 2015

(2) Sampson et al. 2016. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 167(6):1469-80. Sampson TR, 2016

(3) 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/early/2013/11/18/000604

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

(5) Beatman et al. 2015. Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain. J Virol. 90(6):2767-82; Beatman EL, 2015

(6) Miller G. 2009. Neurodegeneration. Could they all be prion diseases? Science. 326(5958):1337-9. Miller G, 2009

(7) Goedert M, Clavaguera F, Tolnay M. 2010. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 33(7):317-25. Goedert M, 2010

(8) Angot et al. 2010. Are synucleinopathies prion-like disorders? Lancet Neurol. 9(11):1128-38. Angot E, 2010

(9) Jucker M, Walker LC. 2013. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 501(7465):45-51. Jucker M, 2013

(10) Prusiner SB. 2013. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet. 47:601-23. Prusiner SB, 2013

(11) Hawkes CH, Del Tredici K, Braak H. 2009. Parkinson's disease: the dual hit theory revisited. Ann N Y Acad Sci. 1170:615-22. Hawkes CH, 2009

(12) Bandea CI. 1986. From prions to prionic viruses. Med Hypotheses. 20(2):139-42. Bândea CI, 1986

(13) Kosik et al. 2016. A path toward understanding neurodegeneration. Science. 353(6302):872-3. Kosik KS, 2016

On 2016 Dec 20, Claudiu Bandea commented:

The etiology of Parkinson's disease is not an enigma

In a recent expert review article entitled “How close are we to revealing the etiology of Parkinson's disease?” (1), Kurt Jellinger concluded: “Although major advances have been made in our understanding of the etiology (and pathogenesis) of PD (and related synucleinopathies) over the last 20 years, it remains as much an enigma as when James Parkinson first described its clinical features” (italics added).

It remains to be seen if the study by Sampson et al. (2) will join the growing list of “major advances” in the field of Parkinson’s, which have revealed numerous contributing factors, including environmental (e.g. toxins), microbial (e.g. various bacteria and viruses), physiological (e.g. oxidative stress) and genetic (e. g. mutations) in addition to the main risk factor - aging.

But what if the etiology of Parkinson’s has remained an enigma primarily because of these “major advances”? What if, by promoting a multitude of different causes and pathogenic mechanisms, each supported by strong data and observations, these “major advances” have led to confusion and have constrained progress? What if Parkinson’s enigma is a classic case of ‘not seeing the forest because of the trees’?

Contrary to the conventional thinking in the field, I recently proposed that the existing data and observations, including those in Sampson et al. (2) and other “major advances”, when integrated in a comprehensive conceptual framework that makes biological and evolutionary sense, point towards a sensible solution to Parkinson’s enigma (3, 4; for recent additional evidence see Ref. 5):

(i) α-synuclein (aSyn), the primary protein implicated in Parkinson’s and related synucleinopathies, is a member of the innate immune system;

(ii) The assembly of αSyn into various oligomers and fibers is not a protein misfolding event as currently defined, nor is it a prion-like replication/propagation activity, but it is an integral part of its biological function in innate immunity;

(iii) The activities associated with the immune function of αSyn lead to Parkinson’s and other synucleinopathies, which are innate autoimmune disorders.

Sampson et al. (2) performed a series of ingenious experiments evaluating the impact of gut microbiota and some of their metabolites on the aggregation of αSyn, activation of microglia, and motor and gut motility deficits in a transgenic mouse model for Parkinson’s that expresses high levels of human αSyn. Similar to other studies showing a strong influence of enteric microbiota on the immune and nervous systems, the results showed that, compared to germ-free transgenic mice, mice carrying complex gut microbiota had increased αSyn associated pathology and microglia activation in the brain and displayed progressive deficit in motor functions and gut motility. The study would have benefited from parallel experiments in mice with disrupted vagal nerve, likely the main portal for αSyn aggregates (as well as for neurotropic microbial/viral pathogens) to the brain, particularly in the light of the finding that the administration of a mixture of short-chain fatty acids, which can reach the brain via the blood circulatory system, simulates the effects of gut microbiota. Perhaps the most intriguing finding reported by Sampson et al. was that the gut microbiota transferred from patients with Parkinson’s enhanced motor impairments, whereas the microbiota from healthy human donors did not, which suggested that the effects might be induced by specific Parkinson’s associated microbial taxa; however, I suggest an additional putative mechanism: the impairment was initiated by ‘αSyn oligomeric seeds’ that were transferred from the patients with Parkinson’s.

As interesting and valuable the results reported Sampson et al. (2) are, the authors have failed to make sense of them in context of the other “major advances” in the field, thereby adding to the enigma (i.e. confusion) regarding the etiology of Parkinson’s and related synucleinopathies.

For example, given that the ‘prion’ concept has been one of the major emerging paradigms in the field of Parkinson’s and other neurodegenerative diseases, including Alzheimer’s, Huntington’s, and ALS (e.g. 5-10), it is highly surprising that Sampson et al. have only mentioned it in the following statement: “Braak’s hypothesis posits that aberrant αSyn accumulation initiates in the gut and propagates via the vagus nerve to the brain in a prion-like fashion (Del Tredici and Braak, 2008)” (italics added). It appears that “Del Tredici and Braak, 2008” reference is a technical error as it doesn’t present a “Braak’s hypothesis”; possibly, Sampson et al. intended to refer to the ‘dual-hit hypothesis’, first presented in 2007 and re-published by the same authors two years later (11). Nevertheless, as I have previously discussed (3,4,12), the ‘prion hypothesis’ is probably flawed, so I commend Sampson et al. for omitting it, but I doubt that the authors were motivated by the same perspective.

I end this brief essay on Sampson et al. (2) by outlining its major weakness, which it is shared with most studies addressing the role of αSyn: the failure to consider the physiological function of αSyn when exploring its pathogenic mechanisms and the etiology of Parkinson’s and related synucleinopathies. Unfortunately, the prion hypothesis and the associated ‘protein misfolding’ paradigm have conceptually uncoupled the pathogenic mechanisms associated with αSyn, as well as with the other main proteins implicated in neurodegeneration (e.g. APP/amyloid-β, tau, huntingtin, TDP-43, prion protein), from their evolutionarily selected biological function (3,4). As recently suggested, the paths toward understanding neurodegeneration must be re-evaluated (13), and this should start with assessing the scientific foundation of the prion hypothesis and protein misfolding paradigm, which are questionable.

References:

(1) Jellinger KA. 2015. How close are we to revealing the etiology of Parkinson's disease? Expert Rev Neurother. 15(10):1105-7. Jellinger KA, 2015

(2) Sampson et al. 2016. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 167(6):1469-80. Sampson TR, 2016

(3) 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/early/2013/11/18/000604

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

(5) Beatman et al. 2015. Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain. J Virol. 90(6):2767-82; Beatman EL, 2015

(6) Miller G. 2009. Neurodegeneration. Could they all be prion diseases? Science. 326(5958):1337-9. Miller G, 2009

(7) Goedert M, Clavaguera F, Tolnay M. 2010. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 33(7):317-25. Goedert M, 2010

(8) Angot et al. 2010. Are synucleinopathies prion-like disorders? Lancet Neurol. 9(11):1128-38. Angot E, 2010

(9) Jucker M, Walker LC. 2013. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 501(7465):45-51. Jucker M, 2013

(10) Prusiner SB. 2013. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet. 47:601-23. Prusiner SB, 2013

(11) Hawkes CH, Del Tredici K, Braak H. 2009. Parkinson's disease: the dual hit theory revisited. Ann N Y Acad Sci. 1170:615-22. Hawkes CH, 2009

(12) Bandea CI. 1986. From prions to prionic viruses. Med Hypotheses. 20(2):139-42. Bândea CI, 1986

(13) Kosik et al. 2016. A path toward understanding neurodegeneration. Science. 353(6302):872-3. Kosik KS, 2016

On 2017 Jan 09, Gerhard Holt commented:

Intimate Cohabitants'Shared Microbiomes and Alpha-Synuclein Pathology

Sampson et al.'s findings on the role of gut microbiota on Alpha-synucleinopathies[1] raise considerable potential concern regarding the microbiome of intimate cohabitants of patients with Alpha-Synuclein pathology, since they are likely to have substantial exposure to a shared microbiome.

Do these intimate cohabitants develop more early Alpha-Synuclein pathology than non-cohabitant controls ?

Are they at greater risk for Parkinson's disease and other alpha-synucleinopathies ?

From an Infectious Disease perspective, this might be an important clinical study.

Perhaps some of the intimate cohabitants are more resistant to A-SYN pathology, SCFAs, or the underlying gut microbes than others - despite similar microbiome exposure ?

Perhaps differences in the interactions between their immune systems and their microbiome alter outcomes ?

This might be a fertile area for differential proteome studies.

Given the importance of Sampson et al.'s findings, hopefully a clinical trial of antibiotics followed by (healthy donor) fecal transplant for patients with Parkinson's Disease will soon follow - perhaps with a cross-over design.

Given the low risks of a potential treatment which uses well known medications and a well established procedure (Fecal Transplant), and given the grossly disproportionate potential benefit, hopefully this study will be expedited in humans.

It may be useful however to also study Alpha-Synuclein pathology in their intimate cohabitants relative to controls.

References :

[1] Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease Sampson, Timothy R. et al. Cell , Volume 167 , Issue 6 , 1469 - 1480.e12

  <www.cell.com/cell/pdf/S0092-8674(16)31590-2.pdf>