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Xmrv brain fog and a lot lot worse

Discussion in 'XMRV Research and Replication Studies' started by Gerwyn, May 7, 2010.

  1. Gerwyn

    Gerwyn Guest

    XMRV inserts into CREB genes causing a mutation.

    CREB is a "KING" regulatory gene is regulates other regulatory genes

    Normal CREB function is essential to keep our brains working properly.

    Downregulating the CREB gene can cause symptoms similar to Altzheimers or Huntington disease

    CREB protects our neurons from environmental "nasties". Downregualtion of CREB is associated with cognitive decline in ageing.Creb is also essential for regulating the autonomic system.

    Nature Genetics 31, 47 - 54 (2002)
    Published online: 22 April 2002; | doi:10.1038/ng882
    Disruption of CREB function in brain leads to neurodegeneration
    Theo Mantamadiotis1, 3, 4, Thomas Lemberger1, 4, Susanne C. Bleckmann1, Heidrun Kern1, Oliver Kretz1, Ana Martin Villalba1, Franois Tronche1, Christoph Kellendonk1, Daniel Gau1, Josef Kapfhammer2, Christiane Otto1, Wolfgang Schmid1 & Gnther Schtz1

    1 Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

    2 Institute of Anatomy, University of Basel, Switzerland.

    3 Present address: Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, 3002, Australia.

    4 These authors contributed equally to this work.
    Correspondence should be addressed to Gnther Schtz g.schuetz@dkfz.de
    Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem -/- background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.

    and some more

    Disruption of CREB function
    Downloaded from www.jbc.org by guest, on April 24, 2010
    specifically interferes with activity dependent synaptic plasticity ranging from long term
    potentiation (LTP) to long-term memory (13-15). It is expected, therefore, that mechanisms that
    interfere with CREB activation would compromise CREB activity dependent neuronal function
    through disruption of downstream gene expression.
    Brain-derived neurotrophic factor (BDNF) is one of the target genes of CREB (17,18).
    BDNF, a member of the neurotrophin family, enhances survival, differentiation and growth of
    certain neuronal populations, modulates synaptic activity and acts as an effector of neuronal
    plasticity both during development and in the adult (20,21). BDNF participates in LTP, is
    upregulated in the hippocampus during learning (22) and deficits in BDNF compromise LTP and
    learning and memory (20). BDNF mRNA and protein are reduced in the hippocampus in AD
    (23-25), a reduction proposed to contribute to cognitive decline observed in AD. Thus,
    examination of BDNF transcription provides a means of assessment of effects on CREB
    regulation, which may play a significant role in the pathogenesis of AD.
    Here, we report that levels of Aβ1-42, which do not affect the survival of cortical neurons,
    may indeed interfere with functions critical for neuronal plasticity, by eliciting a reduction of the
    activity-dependent phosphorylation of CREB and the expression of BDNF, one of the important
    target genes of this transcription factor.
    Downloaded from www.jbc.org by guest, on April 24, 2010
  2. JT1024

    JT1024 Senior Member


    I am usually thrilled with the information you find.... Not the case with this one.

    I will refrain from using the four letter word that immediately came to mind when I read this.

    My brain is already mush today....
  3. Rosemary

    Rosemary Senior Member

    Niemann Pick Type C disease, is commonly referred to as "Childhood Alzheimer’s"

    Please Read:-

    The Connection Between HIV/AIDS, Niemann Pick Type C Gene and Cyclodextrin Sugar Compound


    In the November 2008 issue of The Scientist, author Alison McCook takes an in-depth look at Niemann Pick Type C disease, commonly referred to as "Childhood Alzheimer’s" and explores the possibility that NPC research could provide insights into the mechanisms of Alzheimer’s disease.

    Read the entire story here.


    " In September 2009, I learned the truth about what else is impacting my twins’ health. Addi and Cassi have been diagnosed with an active infection of the newly discovered retrovirus called XMRV, or Xenotropic murine leukemia virus-related virus (confirmed by two labs). XMRV has been linked to Prostate Cancer and Chronic Fatigue Syndrome and millions of people are infected with it just like Addi and Cassi and don’t even know it! Scary! "

  4. Rosemary

    Rosemary Senior Member

    " Niemann Pick Type C disease, is commonly referred to as "Childhood Alzheimer’s" and NPC research could provide insights into the mechanisms of Alzheimer’s disease. "

    Could it be connected to the ATP synthase defects in NPC ? ....There are ATP synthase defects in Alzheimers Disease

    Neuroscience. 2003;117(2):293-303.

    Association of ATP synthase alpha-chain with neurofibrillary degeneration in Alzheimer's disease.
    Sergeant N, Wattez A, Galvn-valencia M, Ghestem A, David JP, Lemoine J, Sautire PE, Dachary J, Mazat JP, Michalski JC, Velours J, Mena-Lpez R, Delacourte A.

    Unite INSERM 422, 1, Place de Verdun, Lille Cedex 59045, France.

    Amyloid deposits and neurofibrillary tangles (NFT) are the two hallmarks that characterize Alzheimer's disease (AD). In order to find the molecular partners of these degenerating processes, we have developed antibodies against insoluble AD brain lesions. One clone, named AD46, detects only NFT. Biochemical and histochemistry analyses demonstrate that the labeled protein accumulating in the cytosol of Alzheimer degenerating neurons is the alpha-chain of the ATP synthase. The cytosolic accumulation of the alpha-chain of ATP synthase is observed even at early stages of neurofibrillary degenerating process. It is specifically observed in degenerating neurons, either alone or tightly associated with aggregates of tau proteins, suggesting that it is a new molecular event related to neurodegeneration. Overall, our results strongly suggest the implication of the alpha-chain of ATP synthase in neurofibrillary degeneration of AD that is illustrated by the cytosolic accumulation of this mitochondrial protein, which belongs to the mitochondrial respiratory system. This regulatory subunit of the respiratory complex V of mitochondria is thus a potential target for therapeutic and diagnostic strategies.
    PMID: 12614671 [PubMed - indexed for MEDLINE]
  5. ramakentesh

    ramakentesh Senior Member

    I thought it was now routinely accept that the brain fog associated with CFS is related to reduced orthostatic brain perfusion...
  6. Rosemary

    Rosemary Senior Member

    Thank you Gerwyn, I think that I now have a better understanding of how decreased Creb regulates mitochondrial gene expression and causes mito dysfunction, and eventual neuronal loss and neurodegeneration

    Summed up nicely here "These results demonstrate that regulation of mitochondrial gene expression by mitochondrial CREB, in part, underlies the protective effects of CREB and raise the possibility that decreased mitochondrial CREB activity contributes to the mitochondrial dysfunction and neuronal loss associated with neurodegenerative disorders. "

    Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival*

    1. Junghee Lee‡,
    2. Chun-Hyung Kim,
    3. David K. Simon∥,
    4. Lyaylya R. Aminova∥,
    5. Alexander Y. Andreyev**,
    6. Yulia E. Kushnareva**,
    7. Anne N. Murphy**,
    8. Bonnie E. Lonze‡‡,
    9. Kwang-Soo Kim,
    10. David D. Ginty‡‡,
    11. Robert J. Ferrante‡,1,
    12. Hoon Ryu‡,1,2 and
    13. Rajiv R. Ratan

    + Author Affiliations

    ‡Neurology, Pathology, and Psychiatry Departments, Boston University School of Medicine, Boston, Massachusetts 02118, the Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, the Molecular Neurobiology Laboratory, McLean Hospital and ∥Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, **Mitochondrial Biology, MitoKor, San Diego, California 92121, the ‡‡Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the Department of Neurology, Weill Medical College of Cornell University and Burke-Cornell Medical Research Institute, White Plains, New York 10605

    1. 2 To whom correspondence should be addressed: GRECC 18B, Bedford Veterans Affairs Medical Center, 200 Springs Rd., Bedford, MA 01730. Tel.: 781-687-2922; Fax: 781-687-3515; E-mail: hoonryu@bu.edu.

    Next Section

    Cyclic AMP response element-binding protein (CREB) is a widely expressed transcription factor whose role in neuronal protection is now well established. Here we report that CREB is present in the mitochondrial matrix of neurons and that it binds directly to cyclic AMP response elements (CREs) found within the mitochondrial genome. Disruption of CREB activity in the mitochondria decreases the expression of a subset of mitochondrial genes, including the ND5 subunit of complex I, down-regulates complex I-dependent mitochondrial respiration, and increases susceptibility to 3-nitropropionic acid, a mitochondrial toxin that induces a clinical and pathological phenotype similar to Huntington disease. These results demonstrate that regulation of mitochondrial gene expression by mitochondrial CREB, in part, underlies the protective effects of CREB and raise the possibility that decreased mitochondrial CREB activity contributes to the mitochondrial dysfunction and neuronal loss associated with neurodegenerative disorders.
  7. Gerwyn

    Gerwyn Guest

    Thanks rosemary anything you come across on CREB or NFAT please send them to me
  8. Gerwyn

    Gerwyn Guest

    no that is a theory it would not explain the range of neurocognitive symptoms
  9. kurt

    kurt Senior Member

    Gerwyn - how could CREB disruption explain the transient nature of brain fog?

    Also, If you have not seen it yet, there is a great list of study references to CREB function and memory on this wiki page:


    This includes one study where experimentally damaged CREB function was restored using viral gene therapy:

    Han et al., "Neuronal competition and selection during memory formation.", Science, 316(5823):457-60
  10. Mithriel

    Mithriel Senior Member

    This is very interesting research.

    I have quite a severe movement disorder. I have paroxysmal dyskinesia, both kinesigenic and non kinesigenic. Basically, I have a bad intention tremor - mentioned in the early reports of ME epidemics - my arms wave about at random, also called choreoathetosis, and my arms will suddenly shoot up in the air (I have given my husband a black eye more than once, oops).

    You can get it with MS and other neurodegenerative illnesses. I have always had neurological symptoms and have felt that a lack of plasticity has been a part of my illness.

    Baclofen and gabapentin have made the movements manageable, I was unable to even feed myself for a while. I also get hyperbaric oxygen treatment which seems to have slowed the progression.

  11. Gerwyn

    Gerwyn Guest

  12. ixchelkali

    ixchelkali Senior Member

    Long Beach, CA
    Gerwyn, in Jonathan Kerr's genomic studies, one of the genes that was upregulated in CFS patients was CREBBP. Is this in some way related to that?

    ...Trying to puzzle my way through microbiology 101 through the brain fog, here...:confused:
  13. Gerwyn

    Gerwyn Guest

    yes There are a few regulatory genes as well
  14. LJS

    LJS Insert Witty Comment Here

    East Coast, USA
    I have been lurking on these forums for some time but decided to post. I have really bad brain fog so excuse if I am reading this wrong but does that mean there is no way to fully recover once you get past a certain point?
  15. flybro

    flybro Senior Member

    wow gerwyn

    messed sleep routines
  16. citybug

    citybug Senior Member

    Hi Gerwyn, Is there a study which links XMRV and CREB? I'd like to show it to my doctor. Thanks kdp
  17. Rosemary

    Rosemary Senior Member

    Yes certainly Gerwyn

    A functional analysis of the CREB signaling pathway .....http://www.biomedcentral.com/1471-2164/10/497

    Viral infection is shown to trigger CREB-mediated upregulation of miR-132....http://www.nature.com/ncb/journal/v12/n5/abs/ncb2054.html?lang=en

    Aparicio-Legarza MI, Reynolds GP, Everitt BJ, Robbins TW. Effects of excitotoxic lesions of the rat prefrontal cortex on CREB regulation and presynaptic markers of dopamine and amino acid function in the nucleus accumbens. Eur J Neurosci, 1999;11: 1265
    [ I shall find link for this ]

    Morphine Induces CREB Phosphorylation....http://www.nature.com/npp/journal/v35/n4/abs/npp2009199a.html

    The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription...

    CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala

    Central Role of Voltage-Gated Calcium Channels
    and Intercellular Calcium Homeostasis in Autism
    (by N.B.S. Lozac, first version published online February 2007)
    part 1:

    Neuronal gene expression A transcription factor is a protein that acts as
    a regulator of gene expression. CREB (cAMP response element-binding)
    proteins are transcription factors which bind to cAMP response elements in DNA
    and thereby increase or decrease the transcription of certain genes. CREB has
    been widely studied due to its role in diverse functions such as circadian
    rhythms, drug addiction and inflammatory pathways. Both CREB and several
    trancsriptional regulators have been linked to epigenetic factors involved
    in cognitive and behavioural developmental disorders [15721740].

    CREB deficient mice for example were shown to exibit less active and
    exploratory behaviours in novel environments, as well as memory deficits in
    spatial learning and fear conditioning [15233759, 15805310].

    One of the ways in which calcium channels influence neuronal and many
    other activities is via signaling pathways that control gene expression. This
    involves regulation of various transcription factors, including CREB.
    Calcium entry specifically through LTCC is particularly important for
    transcriptional responses in neurons, muscle, pancreatic beta cells and osteoblasts.
    Through its stimulation of CREB nuclear calcium may modulate the expression
    of numerous genes including neurotransmitter receptors and transmembrane
    and scaffolding proteins, with the involvement of most having been implicated
    in autism (see Neurotransmitters and Genetic-Factors)

    With regards to BDNF, its levels and levels of BDNF autoantibodies are
    known to be elevated in brains of individuals with autism, with one study
    observing them to be three times higher than controls, with on the other hand
    significantly reduced blood levels in adults with autism [16181614,
    11431227, 16876305]. Excessive activation of LTCC causes granule cells to express
    BDNF, the release of which stimulates tyrosine kinase receptors (Trk)B to
    induce axonal branching, which may establish hyperexcitable dentate circuits
    implicated in epilepsy [15317847]. Exploring TrkB partial agonists as a
    possible treatment option for autism has been suggested [16023301]. The
    mechanism of calcium and BDNF signalling also plays a role in establishing
    granule cell synaptic transmission, including levels of expression of NMDA
    receptors, during cerebellar development [16221864].
    Apart from BDNF, its neurotrophin family includes the growth factors Nerve
    Growth Factor (NGF) neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4), some
    of which were also found to be elevated in autism in several studies
    [11357950, 16289943]. The same studies observed raised levels of neuropeptide
    vasoactive intestinal peptide (VIP) compared to controls. The expression
    level of VIP is influenced by calcium influx through LTCC, possibly through
    similar mechanisms [15197736].
    On the other hand VIP is able to influence VGCC conductance through its
    known interaction with
    G-protein-coupled receptors [8772132, 15109935].
    In addition, significant elevations of neuropeptide vasopressin (AVP),
    with concurent reductions in
    levels of apenin, a neuropetide that could counteract AVP action, have
    been observed in autism.
    Again the involvement of raised calcium levels and CREB activities has
    been suggested in the
    expression of vasopressin gene [3607454, 9389510].
    Possible involvement of Homer and Shank protein complexes in the LTCC
    activation of CREB has
    been suggested [15689539, 12716953], as localized calcium responses,
    regulated by interactions
    with PDZ domain proteins, are deemed necessary for this activation. It
    should be mentioned that
    loss of the SHANK3/PROSAP2 gene has been proposed to be responsible for
    the main neurological
    developmental deficits observed in 22q13 deletion syndrome, characterised
    by delays in speech
    and motor deveopment [16284256] (see Genetic-Factors) . Chromosomal
    deletions of SHANK3
    have recently been identified in a small number of individuals with
    With reference to CREB-related activities possibly being relevant in the
    etiology of autism, it
    should be added that sex hormone estradiol has been noted to regulate CREB
    activity via its direct
    and/or indirect effect on LTCC, and that considerable overlap between
    behaviors and processes
    reliant on CREB and those that are influenced by estradiol has been noted
    [15901789] (see Gender Differences) .
  18. Mithriel

    Mithriel Senior Member

    Have I got this right?

    Is increased phosphorylation a good thing?

    I take tramadol as a painkiller. It helps stop muscle painful muscle spasms rather than take the pain away. Unfortunately t makes it hard for me to sleep so I can only take 1 in the morning.

    However, it has made me feel much better, less flu like and I can do more, without payback. This is when I can use the computer for instance.

  19. flybro

    flybro Senior Member

    My life improved dramatically when I started taking tramadol, and my sleep imrpoved on it. It seemed to help with my twitchy bladder.

    When my Doc prescribed them for me, she told me I had to take 4 aday and had to stay on them for a week.

    I'm glad she was firm about it, I felt floaty and stoned for the first week, it was lovely, but completley non functional.

    Now I take upto eight a day depending on how active I'm going to be, on a normal day not to active, I'll take 4 a day.

    They make everything feel that bit easier, I still have bouts of pain, but \I have much less constant aching pain and twitchyness.

    Morphine Induces CREB Phosphorylation and this is a good thing yes?

    I'm intrested because I cant have morphine, it seems to make me more sensitive to pain.

    I've had it twice and they had to change down to something like voltarol which did work, where the morphine had me in tears.
  20. Xander



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