Cerebrospinal fluid (CSF) proteomics

[Robert 1973]

Discussion split from discussion of an NIH webinar where there was a presentation of a forthcoming Bergquist CSF proteomics study USA: NIH National Institutes of Health news

I don't remember seeing proteomics done on CSF before, looking forward to seeing the results in full.

Does anyone know if CSF proteomics has been used to study other illnesses?

 

[Dolphin]

I don't remember seeing proteomics done on CSF before, looking forward to seeing the results in full.

There was this study:
A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid
James N Baraniuk et al. BMC Neurol. 2005.
https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-5-22

 

[duncan]

Does anyone know if CSF proteomics has been used to study other illnesses?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9632922/

https://pubs.acs.org/doi/10.1021/pr300577p

 

[Dolphin]

There was this study:
A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid
James N Baraniuk et al. BMC Neurol. 2005.
https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-5-22

Also
Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome
Steven E Schutzer et al. PLoS One. 2011.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

 

[duncan]

Small world.

I was recruited for this for the CFS cohort, and also considered for the PTLD part; I declined regardless:

Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome

And I was in a subsequent one to this below with the Georgetown U folks.

A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid

 

[SNT Gatchaman]

Does anyone know if CSF proteomics has been used to study other illnesses?

Some recent papers in neurodegenerative diseases, esp AD —

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease (2023, Nature Medicine)
Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer’s disease (2023, Science Translational Medicine)
Meta-analysis of published cerebrospinal fluid proteomics data identifies and validates metabolic enzyme panel as Alzheimer’s disease biomarkers (2023, Cell Reports Medicine)
CSF proteome profiling across the Alzheimer’s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels (2022, Nature Aging)
Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease (2022, Cell Reports Medicine)
Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease (2020, Science Advances)

 

[dreampop]

I hope that's meant in the scientific sense not the BPS sense

I don't think I know the BPS sense of it, probably for the best.


The Baraniuk study uses a very confusing and problematic definition of CFS.

There was also a CSF metabolomics that I was excited about, from Fiehn Columbia, which was never published. I could've sworn it was in one of Cornell or Columbia's proposed studies for their NIH Center for Excellence grants.

 

[Hutan]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes 2022, Schutzer et al
There was this recent paper, also from the Bergquist team. Forum members were generally underwhelmed, mainly due to the lack of a healthy control comparison. It's good to see that the latest Bergquist study includes not only ME/CFS and Long Covid cohorts, but also a healthy control cohort.

The post-treatment Lyme disease study was also from the Bergquist team.

(sorry for late edits)

 

[SNT Gatchaman]

Promising.

I hope that's meant in the scientific sense not the BPS sense

I don't think I know the BPS sense of it, probably for the best.

It's a reference to the frequent use of the word "promising" to describe BPS findings that are at best modest; but more realistically reflecting natural recovery, regression to mean, hopelessly confusion by uncontrolled expectation bias and generally incompetent methodology, and the muddled thinking exemplified by frequent correlation/causation confusion.

Also CSF proteomics is going to really challenge editors now that we'll have more "ME/CFS CSF" studies. Hopefully the findings will help get us to a definitive disease name soon

 

[leokitten]

Does anyone know if CSF proteomics has been used to study other illnesses?

Parkinson’s, MS

 

[dreampop]

Also CSF proteomics is going to really challenge editors now that we'll have more "ME/CFS CSF" studies. Hopefully the findings will help get us to a definitive disease name soon

Now that I can absolutely confirm. It's definitely made me double and triple check my comments over the years.

 

[FMMM1]

I assume someone's posted a link to Jonas's Twitter post -

 

[Milo]

Moved post

I don't remember seeing proteomics done on CSF before, looking forward to seeing the results in full.

It was done several years ago, pooled csf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044169/
Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome
Steven E. Schutzer,# 1 , * Thomas E. Angel,# 4 Tao Liu,# 4 Athena A. Schepmoes, 4 Therese R. Clauss, 4Joshua N. Adkins, 4 David G. Camp, II, 4 Bart K. Holland, 3 Jonas Bergquist, 5 Patricia K. Coyle, 6Richard D. Smith, 4 Brian A. Fallon, 7 and Benjamin H. Natelson 2 , 8

 

[mariovitali]

There was this study:
A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid
James N Baraniuk et al. BMC Neurol. 2005.
https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-5-22

Regarding the paper above. From the study, we read :

This pilot investigation demonstrated that the CFS, PGI and FM subjects had a significant overlap between their syndromes. Despite the differences in their original case designations, they had very similar responses on questionnaire, quality of life and nociceptive measures. Again, despite the differences in the diagnostic label applied to them for study entry, their cerebrospinal fluid proteomes demonstrated reproducible constituents. The CFS – related proteome was essentially the same for the two independent CFS cohorts. The proteome was remarkable for the number of proteins associated with protein misfolding and cerebrovascular amyloidosis syndromes. These included gelsolin, amyloid β protein (APLP1), Ig λ, C3, C4, chromogranin B, α2-macroglobulin and α-1-antichymotrypsin antiproteases, the heme and iron scavengers haptoglobin, hemopexin, and orosomucoid 2, angiogenic and antiangiogenic prohormones such as autotaxin and PEDF, and the structural proteins gelsolin, BEHAB and keratin 16. Their presence in the CFS – associated proteome suggested a potential pathophysiological link. We propose the hypothesis that CFS may be a nonlethal, protein – misfolding, cerebrovascular amyloidosis – like syndrome.

@Jonathan Edwards would you say that given the numerous studies pointing to protein folding issues, Endoplasmic reticulum stress appears to be a key mechanism for the symptoms of ME/CFS?

 

[Jonathan Edwards]

@Jonathan Edwards would you say that given the numerous studies pointing to protein folding issues, Endoplasmic reticulum stress appears to be a key mechanism for the symptoms of ME/CFS?

I have no idea but I don't think the 'protein misfolding' in amyloid has anything to do with ER stress does it? (I have never been quite sure what ER stress is supposed to be.)

 

[SNT Gatchaman]

As I understand it ER stress is the overload of the endoplasmic reticulum system by mis-folded proteins: too many mis-folded proteins or too little functional resource in the ER to deal with them. The stress might be eg induced by viral hijacking, forcing cell machinery to Make More Proteins, a proportion of which fail quality control. Amyloid proteins are a subset of incorrectly folded (mis-folded or unfolded) proteins I would think — with the protein's secondary structure favouring beta-pleated sheets rather than alpha-helices IIRC.

From Type I interferons and endoplasmic reticulum stress in health and disease (2020, International Review of Cell and Molecular Biology, PMC) —

the ER is an important organelle that is accountable for the production, maturation and posttranslational modifications of a number of proteins. Moreover, a number of pathological perturbations that can elicit type I IFNs also tend to affect ER homeostasis, e.g., chemotherapeutic or radiotherapeutic stress, oxidative injury, and microbial infections (especially of viral origin). Such interference with ER homeostasis compromises ER-associated proteostasis thereby causing ER stress. The ER typically responds to such insults by stimulating a complex signaling cascade, called the unfolded protein response (UPR). Herein, the primary aim of the UPR is to overcome “proteotoxicity” and rescue ER homeostasis thereby prolonging cellular survival. However this primary aim is only met in conditions of low-to medium ER stress such that severe ER stress almost always steers the UPR to engage pro-death signaling […] Due to the overlaps between type I IFNs production or sensing and the ER, not surprisingly, ER stress has critical consequences for type I IFNs-associated functions. Moreover, even type I IFNs themselves are capable of eliciting ER stress in target cells, given the right conditions.

In relation to ER stress in ME/CFS the WASF3 paper said —

Increased ER stress would normally be expected to turn down protein translation, but intriguingly, the inhibitory phosphorylation of protein translation factor eIF2α, a target of PERK kinase activity, was unexpectedly lower (i.e., activated) in patient S1 cells. This finding suggested that there was “ER stress response failure” in patient S1 cells as also observed in the ME/CFS muscle biopsy samples

 

[Jonathan Edwards]

In relation to ER stress in ME/CFS the WASF3 paper said

To me, that quote suggests that nobody actually knows what they mean by ER stress here. If it is due to too many misfolded proteins then the misfolded proteins are not a sign of er stress but a sign of something else, stressing the ER maybe. Words like 'stress' in this context have no precise dynamic meaning. They are anthropomorphisms or teleologies. The same goes for oxidative stress. It is used to mean something in hypothesising that the technical definition doesn't actually mean. So everyone goes round wisely nodding about oxidative stress but after forty years nobody has ever established its relevance to anything much.