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Thread: The Promise of the Proteome-New Technology Catalogues Proteins In Spinal Fluid CFIDS

  1. #1
    Veteran Member Reesacat's Avatar
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    24th September 2007
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    Default The Promise of the Proteome-New Technology Catalogues Proteins In Spinal Fluid CFIDS

    The Promise of the Proteome
    Analysis of the PLoS ONE paper
    February 23, 2011

    Today, February 23, 2011, in the online journal PLoS ONE, researchers from six institutions published a
    tantalizing study that uses powerful discovery technology to catalogue proteins in chronic fatigue
    syndrome (CFS) and neurologic post-treatment Lyme disease (nPTLS) spinal fluid samples. The exciting
    work is the product of a large team led by Steven Schutzer at the University of Medicine and Dentistry of New Jersey and Thomas Angel and Tao Liu of the Pacific Northwest National Laboratory.

    In an article titled, “Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease
    and CFS,” Schutzer and colleagues tested samples collected by lumbar puncture from 43 CFS subjects
    carefully evaluated using 1994 Fukuda criteria, 25 subjects who met CDC surveillance criteria for Lyme
    disease and who had completed at least three weeks of intravenous antibiotic therapy at least four
    months earlier, and 11 healthy controls. The disease comparison groups were chosen because of the
    overlap of central nervous system (CNS)-related symptoms and lack of medical explanation for either
    CFS or nPTLS. They write, “Specific abnormalities found in cerebrospinal fluid (CSF) relating to CFS and
    nPTLS would suggest CNS involvement, and could facilitate mechanistic understanding.”

    The investigators combined two powerful technologies called mass spectroscopy and liquid
    chromatography to analyze the CSF samples. Mass spectroscopy is a tool that measures the mass of
    particles and thus the composition of a sample. Liquid chromatography measures the relative proportions of particles in a mixture. This
    combination of methods was chosen for its ability to cast a wide “discovery” net in the
    analysis of complex biological specimens, without having to define in advance what proteins might be present. The group recently established a
    comprehensive normal “proteome” as a baseline for comparison to disease samples. The term proteome refers to the entire set of proteins found in a biological sample; in this case, cerebrospinal fluid. Proteins are made up of smaller particles called peptides.
    Using these tests the team was able to generate a comprehensive list of 30,000 peptides in the samples pooled from subjects in each disease group. Of these 30,000 peptides, 738 proteins were found only in CFS subjects (Figure 1). The nPTLS samples had 692 unique proteins and the normal controls had 724 unique proteins. Differences in the amounts of various proteins were detected between groups and CFS and nPTLS
    had more proteins in common than with the healthy controls.
    Figure 1: Venn diagram illustrating distribution of proteins
    identified in the three groupsLooking at the biological pathways implicated by the different proteins identified, the team found that
    proteins in the complement cascade were elevated in abundance in the pooled nPTLS and CFS samples
    compared to controls, but at different levels for the disease groups. The complement system is a part of
    the immune system that helps to clear infectious pathogens. Interestingly, in a 2005 proteomics study conducted by James N. Baraniuk and published in BMC Neurology, the complement system proteins were also found in cerebrospinal fluid from CFS patients and differentiated CFS patients from healthy controls.
    Alterations in the complement cascade pathways have been a relatively consistent
    abnormality in CFS patients (Sorensen B, et al., 2003 and 2009). This convergence of data implicates biomarkers and pathways that should be prioritized for verification and validation.
    Proteins involved in the CDK5 signaling pathway were significantly enriched in the CFS samples. Alterations in the CDK5 signaling pathway have been linked to Parkinson’s disease and Alzheimer’s disease.
    Proteins relevant to specific neurological functions were lower in CFS than nPTLS, and both disease groups had lower levels than the healthy controls. The authors recognized that the clinical
    significance of the proteins and protein levels identified in the sample groups is “difficult to determine in
    the discovery phase.”

    They also examined individual CSF
    samples (rather than pooled
    samples) from CFS and nPTLS
    subjects. In doing so, they
    identified a set of proteins that
    distinguished the two disease
    states (Figure 2A and 2B). By
    analyzing individual CSF samples,
    they determined that nPTLS
    patients are distinct from CFS
    patients. The ability to distinguish
    CFS and nPTLS on the basis of
    these proteins has important
    diagnostic implications. Because
    the etiologic agent for Lyme
    disease is known to be Borrelia
    burgdorferi, this finding suggests
    distinct pathophysiologies for
    these two clinically similar
    diseases. It also suggests different
    treatment approaches may be warranted. Some have proposed that nPTLS represents a subset of CFS;
    however, the authors of this paper conclude that their data does not support that concept.
    In the final discussion section, the authors state, “CSF proteome analysis may provide important and
    meaningful insights into the biological processes modulated as a function of disease and facilitate the
    identification of protein candidates for further investigation…Distinguishing CFS and nPTLS will have
    etiologic implications which could lead to novel diagnostics and therapeutic interventions.” They suggest
    that by uncovering these candidates in cerebrospinal fluid, a targeted search in blood for these proteins
    is now possible.
    Figure 2: Comparative analyses of the individual CFS and nPTLS
    proteomesThis team of researchers provided the comprehensive list of proteins they identified as part of the open
    access paper. This will enable these and other investigators to explore and interrogate the data further.
    This list of proteins can immediately be put in the context of other findings in the CFS literature using
    cutting-edge computational and text mining tools. It could rapidly accelerate the identification of the
    most promising proteins and pathways for generating objective diagnostic assays and targeted

    The Association’s scientific director, Suzanne D. Vernon, PhD, notes, “I am particularly excited about this
    study and the new avenues it opens. Pairing this treasure trove list of proteins with the biological and
    clinical resources in the Association’s SolveCFS BioBank will quicken the pace at which these biomarkers
    can be verified and validated, hopefully shortening the pipeline from benchside discovery to bedside
    application. The contributions made by this group to understanding the biology of CFS and nPTLS could
    not have come at a more timely moment for the field and the patient community.” The firestorm
    generated by last week’s publication of the U.K.’s injurious PACE Trial and uncertainty about the role of
    XMRV/MLVs in CFS have taken a toll on patients, advocates and researchers alike.
    The study is a model for partnership across multiple institutions and funding agencies. It was supported
    by the National Institutes of Health (National Institute of Allergy and Infectious Diseases, National
    Institute on Drug Abuse, National Institute of Neurologic Diseases and Stroke and the National Center
    for Research Resources), the Swedish Research Council, Uppsala Berzelii Technology Center for
    Neurodiagnostics, SciLifeLab-Uppsala, Time for Lyme, Lyme Disease Association and the Tami Fund. The Pacific Northwest National Laboratory is a national scientific user facility sponsored by the Department of Energy. CFS patients were identified and evaluated by Benjamin Natelson at Albert Einstein School of Medicine. Lyme patients were identified and evaluated by Brian Fallon at Columbia University. Jonas Berquist of Uppsala University in Sweden assisted with data analysis. The collaborative effort, use of new technologies for discovery and willingness to openly share data to advance the field represent an inspiring 21st century research initiative worthy of high hopes.

    The CFIDS Association of America is committed to advancing research that leads to the early detection, objective diagnosis and effective treatment of CFS. The scientific and medical communities are obligated to understand the biological roots of CFS so that targeted and effective treatments can be made available to the millions of people around the world whose lives have been derailed by CFS.
    Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins NJ, Camp DG, Holland BK, Bergquist J,
    Coyle PK, Smith RD, Fallon BA, Natelson BH. (2011) Distinct cerebrospinal fluid proteomes differentiate
    post-treatment Lyme disease from chronic fatigue syndrome. PLoS ONE 6(2): e17287.
    Baraniuk JN, Casado B, Maibach H, Clauw DJ, Pannell LK, Hess S. (2005) A chronic fatigue syndrome -
    related proteome in human cerebrospinal fluid. BMC Neurology 2005, 5:22doi:10.1186/1471-2377-5-22
    Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF. Complement activation in a
    model of chronic fatigue syndrome. Journal of Allergy and Clinical Immunology. 2003 Aug;112(2):397-
    Sorensen B, Jones JF, Vernon SD, Rajeevan MS. Transcriptional control of complement activation in an
    exercise model of chronic fatigue syndrome. Molecular Medicine. 2009 Jan-Feb;15(1-2)
    Last edited by Islander; 02-24-11 at 12:26 AM.

  2. #2
    Veteran Member mellowsong's Avatar
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    24th September 2007
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    Default Re: The Promise of the Proteome-New Technology Catalogues Proteins In Spinal Fluid CF

    I had a spinal tap in 1999 for what turned out to be viral meningitis (Epstein-Barr). I also remember though, that I was told there was a lot of protein in my CSF but they didn't really know why. I was diagnosed with CFIDS about a year or so after this episode.

  3. #3
    Veteran Member Reesacat's Avatar
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    24th September 2007
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    Default Re: The Promise of the Proteome-New Technology Catalogues Proteins In Spinal Fluid CF

    For a brief CBS video on this study:

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