Xmrv brain fog and a lot lot worse

G

Gerwyn

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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.



Article
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
4
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
 

JT1024

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Gerwyn,

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....
 

Rosemary

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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

http://addiandcassi.com/

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.

http://addiandcassi.com/thescientistcover/


" 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! "

http://addiandcassi.com/does-xmrv-u...fected-children-may-teach-us-about-the-virus/
 

Rosemary

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" 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.

Abstract
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]
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

http://addiandcassi.com/

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.

http://addiandcassi.com/thescientistcover/


" 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! "

http://addiandcassi.com/does-xmrv-u...fected-children-may-teach-us-about-the-virus/
 

ramakentesh

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

Rosemary

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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

1.
‡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
Abstract

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.
 
G

Gerwyn

Guest
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

1.
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
Abstract

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

kurt

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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:

http://en.wikipedia.org/wiki/CREB_in_Molecular_and_Cellular_Cognition

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
 

Mithriel

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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.

Mithriel
 
G

Gerwyn

Guest
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:

http://en.wikipedia.org/wiki/CREB_in_Molecular_and_Cellular_Cognition

I am talking about neurocognitive dysfunction there is nothing transient about that.If you just have occasional brainfog whatever that is then you are lucky.Creb has some complex neuro protective functions and regulates other genes that regulate neurocognitive function.It also plays akey part in the immune system and endocrine function.I have some 40 papers already thanks. It plays a key role in several neurodegenerative disorders. It also plays a key role in maintenance of circardian rhythms
 

ixchelkali

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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:
 
G

Gerwyn

Guest
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:
yes There are a few regulatory genes as well
 

LJS

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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?
 

citybug

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

Rosemary

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Thanks rosemary anything you come across on CREB or NFAT please send them to me
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...
http://www.nature.com/onc/journal/v29/n14/abs/onc2009498a.html

CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala
http://www.nature.com/neuro/journal/v12/n11/abs/nn.2405.html?lang=en

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
autism.
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) .
 

Mithriel

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Have I got this right?

Morphine Induces CREB Phosphorylation
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.

Mithriel
 

flybro

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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.

Mithriel
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.