Sunday, March 23, 2014

Is neurofibrosis set off by a nerve virus type of autoimmune disease?

Thinking that the genetic component is "released" under autoimmune circumstances. 

Merlin (focus will be on this and autoimmune disease...could reveal more of the overlap problem of the immune system leading to autoimmune disease)
http://www.ncbi.nlm.nih.gov/pubmed/17721284

neurofibrosis and MS.....herpes zoster
http://www.ncbi.nlm.nih.gov/pubmed/7745407
http://www.ncbi.nlm.nih.gov/pubmed/20424878

Guillian Barre? none found...yet
however lung cancer does appear
Merlin was connected to mesothelioma
http://www.stemcellsfreak.com/2014/02/mesothelioma-cancer-stem-cells.html 
http://www.ncbi.nlm.nih.gov/pubmed/23939548
http://www.ncbi.nlm.nih.gov/pubmed/11132929

Guillian Barre typically follows a gastrointestinal infection or a lung infection....if Campylobacter jejuni is the intestinal infection that eventually infects the peripheral nerves what is the lung infection? Mycoplasma pneumonia?

Mycoplasma pneumonia, guillian barre, and peripheral nerves
http://www.aocn2012.com/abstract/71.asp 

Autism...measles virus
http://www.wrongplanet.net/postt128815.html (60% of NF kids have autism?)
http://www.ncbi.nlm.nih.gov/pubmed/24190681
http://www.ncbi.nlm.nih.gov/pubmed/23163951
http://www.ncbi.nlm.nih.gov/pubmed/23163236


Saturday, March 22, 2014

Autoimmunity: layered attack of the immune system by cross-targeting or cross-reactivity with molecular mimicry

This is a hypothesis blog and not proven...yet. 

Molecular mimicry is when an infection's protein looks like a host's protein.  (they are not the same but close enough the antibody flags mark them)

Cross-reactivity is when 2 different infections have the same protein causing the immune system to overlap. (A cross-target of a protein) If the host has the same protein or molecular mimicry is occurring autoimmunity would develop.

 example : Hemagglutinin is on mycoplasma gallispeticum and on flu viruses. Infections use hemagglutinin to bind host receptors which then allow them to enter host cells.

Cross-targeting is when 2 different types of infections cause the immune system to target the same organ or cell type.  An example would be the pancreas in type one diabetes: mycoplasmas could infect the pancreas then a flu virus replicates in it.

(viruses replicate and infect only some cell types and this will correspond to the autoimmune diseases they trigger) 


It is my hypothesis that autoimmunity occurs when for some reason the immune system overlaps on self.

Wednesday, March 19, 2014

Anti-cardiolipin antibodies and the infections with cardiolipin

This page is still under construction:

I just want to clarify with this blog post that the infections I have associated with these cardiolipin associated diseases do in fact have cardiolipin in them. 

Cardiolipin is found in gram positive bacteria. Mycoplasmas evolved from gram positive bacteria.

Found cardiolipin in mycoplasmas
http://www.hindawi.com/journals/jl/2012/640762/

RA and lupus associated with mycoplasmas
http://angelabiggs.blogspot.com/2013/04/lupus-and-ra-leukemia-and-mycoplasmas.html

cardiolipin is also found in anti-phospholipid syndrome..which i have associated with mycoplasmas
http://angelabiggs.blogspot.com/2013/12/antiphospholipids-and-infections-with.html

Strep and cardiolipins
http://ard.bmj.com/content/61/4/374.full.pdf+html

Behcets has anti-cardiolipin and is associated with strep
http://angelabiggs.blogspot.com/2013/04/behcets-disease.html

cryptococcus neoformus and cardiolipin
http://www.ncbi.nlm.nih.gov/pubmed/6392829

scleroderma has anti-cardiolipin and is associated with cryptococcus neoformus
http://angelabiggs.blogspot.com/2014/02/is-scleroderma-autoimmune-disease.html

 

Friday, March 14, 2014

Rescued app paper from ALZforum : written years ago but still interesting

Growth or No Growth: APP Weighs the Question

Angela Biggs Proposes a Biological Function for APP

First, consider the two forms of APP. The membrane AβPP form has a receptor-like protease(1) with a cytoplasmic region capable of binding small G-proteins.(2) In neurons, the membrane form is found at the synaptic zone at the tip of growth.(3,4) The secreted form of APP is an extracellular protease that has been shown to stimulate neurite extension.
Now consider that AβPP is also known as protease nexin II, a serine protease.(5,6,7) The serine protease inhibitor neuroserpin has been shown in PC12 cells not only to decrease the length of neural axon extensions, but also to stop axon growth altogether.(11)
I propose that the biological function of APP appears to be to act as a serine protease to "switch" neurons into the growth mode.
To weigh this idea, discoveries in other cell types should be considered: Maspins are serine protease inhibitors that insert into the membrane and control the cytoskeleton; without maspins, breast cancer cells metastasize.(8)
Next, consider that P53 turns on maspin expression by binding DNA.(9) Note that p53 binding is also required for bcl-2 expression. In neurons, AβPP seems to prevent p53 from binding to DNA.(10) So serpins and serine proteases have opposite relationships with P53. This makes sense because p53 binding protects quiescent neurons from apoptosis via bcl-2, while rapidly growing neurons could be easily eliminated if needed.(14)
Neuroserpins and α-1-antichymotrypsin (α-1-ACT) are serine protease inhibitors that could be acting as maspins. Interestingly, expression of APP and α-1-ACT have been shown to coexist together in the membrane of human skeletal muscle.(12)—a serine protease receptor with a serine protease inhibitor receptor.
Putting it all together, there seem to be two critical states of neurons: those that are growing and using serine proteases to do so, and those that are quiescent. Growing neurons would be using APP pathways, possibly through RhoG (a small G-protein) to extend microtubules, whereas quiescent neurons would use the membrane serpin. I speculate that serpins may act through RhoA to dictate a non-growth cytoskeletal structure.(13)
APP and Cholesterol
Another nice feature of this proposed APP function as a controller of "growth of non-growth" is that it explains the cholesterol relationship. The elongated membrane of the nerve growth cone would require more cholesterol in the membrane for structural stability. Simple membrane structures require less cholesterol, while complex membrane structures require more. The addition of cholesterol to membranes stabilizes the lipids, thus preventing them from floating away.(15) If the body wanted to get rid of cholesterol, it might attempt to use as much as possible in complex membranes like those of growing axons and growth cones.
For example, treating APP-transfected HEK cells with statin drugs reduced the processing of newly synthesized APP. Adding cholesterol to the HEK cells increased BACE cleavage of APP by fourfold.(16) The cells appear to choose the APP pathway in order to use cholesterol in the membrane!
What about the decrease of the α-secretase processing of APP? My understanding is that there are two main types of APP cleavage, α and β. Transgenic mice overexpressing APP when exposed to high cholesterol show an increase of the β-secretase cleavage of APP and a decrease of α-secretase cleavage.(17) Since α-secretase cleavage occurs at the membrane surface of neurons,(18) I suggest that this α cleavage might be an "off cleavage." Could it also be that neuroserpin inhibits APP, then the secretase cleaves it, turning the growth mode of the APP receptor off permanently, then stimulating the nerves nearby as if to take turns growing?
I reason that high cholesterol would push neurons into the APP cytoskeleton growing mode, which uses cholesterol in the membrane. Problems could occur once the neuron could no longer keep up the growing pace, or too much Aβ was made due to high cholesterol stimulating APP production. If the nerve became stuck in the growth mode, it makes sense that proteins used in growth could pile up; this includes APP, tau,(21) and α-synuclein as a plasma membrane omega fatty acid transporter.(22)
APP and Dementia
Another appealing feature of APP functioning as a serine protease and the neuron switching into a growth mode is that it might also help explain dementia and the neuron's mitochondria. Assuming that the mitochondria must be coordinated with neuron growth and division, it is interesting to note that the transmembrane protease called rhomboid responsible for the proteolysis of mitochondrial membranes is a serine protease.(19) So a serine protease in mitochondrial membranes appears to remodel the mitochondria from the mesh system into "portable, hotdog-like" organelles. I am suggesting that when APP, a plasma membrane serine protease receptor, switches the neuron to a growth mode, somehow a serine protease in the mitochondrial membrane is also switched on.
Where does this line of thought lead? Mitochondria have been called the "memory" of neurons, as they use their calcium stores to record stimulation and adjust neurotransmitter release based on stimulation.(20) Wouldn't it be interesting if the morphology of the mitochondria affected this calcium memory property? For instance, if the mitochondria are in the mesh form, the neuron can "remember," but when mitochondria are in the hot dog form during serine protease expression, the neuron cannot. This is, in effect, a speculation that sudden returnable memory relates to the state of the mitochondria. It is unknown whether the APP serine protease in the plasma membrane is coordinated with the mitochondrial serine protease, but the fact that they are both transmembrane serine proteases is suggestive. Could APP trigger dementia by causing the mitochondrial serine protease to be expressed?
Consider resveratrol, the polyphenolic compound of red wine, cranberries, and blueberries. Resveratrol has been found to slow the growth of prostate cancer cells.(23) Serine protease inhibitors—the serpins—use their phenol groups to inhibit the serine proteases. Could the return of memory that occurs with blueberries and other resveratrol-containing foods actually be due to resveratrol acting like a serpin, thus inhibiting the serine protease of the mitochondria and allowing the mitochondria to form back into a mesh?
There are a lot of possibilities with this growth model of APP as a serine protease. I hope enterprising scientists will take up testing it! —Angela Biggs, Independent Researcher.
Please note: Just in case it is not mentioned in the live discussion, I would like to note that clioquinol is an antifungal and it is not entirely understood how it is working in Alzheimer's patients.
References:
1. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. Abstract
2. Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o) Nature. 1993 Mar 4;362(6415):75-9. Abstract
3. Schubert D. The possible role of adhesion in synaptic modification. Trends Neurosci. 1991 Apr;14(4):127-30. Review. No abstract available. Abstract
4. Levitan and Kaczmarek. 1991. The Neuron. pp 343-344.
5. Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ. Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci. 1995 Mar;15(3 Pt 2):2157-67. Abstract
6. Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, Otero DA, Saitoh T. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci. 1994 Sep;14(9):5461-70. Abstract
7. Oltersdorf T, Fritz LC, Schenk DB, Lieberburg I, Johnson-Wood KL, Beattie EC, Ward PJ, Blacher RW, Dovey HF, Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144-7. Abstract
8. Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11669-74. Abstract
9. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem. 2000 Mar 3;275(9):6051-4. Abstract
10. Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7547-52. Abstract
11. Parmar PK, Coates LC, Pearson JF, Hill RM, Birch NP. Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells. J Neurochem. 2002 Sep;82(6):1406-15. Abstract
12. Akaaboune M, Ma J, Festoff BW, Greenberg BD, Hantai D. Neurotrophic regulation of mouse muscle beta-amyloid protein precursor and alpha 1-antichymotrypsin as revealed by axotomy. J Neurobiol. 1994 May;25(5):503-14. Abstract and Akaaboune M, Verdiere-Sahuque M, Lachkar S, Festoff BW, Hantai D. Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro. J Cell Physiol. 1995 Dec;165(3):503-11. Abstract
13. Vignal E, Blangy A, Martin M, Gauthier-Rouviere C, Fort P. Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Mol Cell Biol. 2001 Dec;21(23):8022-34. Abstract
14. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci. 2003 Oct 15;116(Pt 20):4077-85. Abstract
15. Alberts et al. 1989. Molecular Biology of the Cell, 2nd edition. pp 279.
16. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999 Jun 3;10(8):1699-705. Abstract
17. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. Erratum in: Neurobiol Dis 2000 Dec;7(6 Pt B):690. Abstract
18. Parvathy S, Hussain I, Karran EH, Turner AJ, Hooper NM. Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells. Biochemistry. 1999 Jul 27;38(30):9728-34. Abstract
19. McQuibban GA, Saurya S, Freeman M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature. 2003 May 29;423(6939):537-41. Abstract
20. Kaczmarek LK. Mitochondrial memory banks. Calcium stores keep a record of neuronal stimulation. J Gen Physiol. 2000 Mar;115(3):347-50. Review. No abstract available. Abstract
21. Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem. 2001 Jan;76(2):391-400. Abstract
22. Pro Natl. Acad Sci USA 98 (16):9110-5.
23. Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5. Abstract

Wednesday, March 12, 2014

LON1 and dimorphic switching caused by gluten or casein? Do 4 different types of infection have Lon? thus 4 types of gluten sensitivity

This post of the blog is going to focus on the LON1 enzyme which in e.coli causes a change in morphology : rod to string (lon stands for LONG ) I am looking for the same change in the other infections I believe to be gluten sensitive.

This page should compliment the 4 types of gluten post if we postulate that gluten and casein act on Lon to change the morphology.

Test of Lon came up negative. It is not gluten sensitive.  Looking at a similar serine protease that is also casein sensitive but when i looked at the list of infections that are gluten sensitive 2 really don't fit t.gondii and strep but all of these infections are "intestine and BBB crossers" so the new theory is Gluten and/or casein merely increase inflammation.  

1. E.coli
In E.coli LON1 can be controlled by casein
REF to come
http://www.ncbi.nlm.nih.gov/pubmed/24520911 (casein acting on Lon)
http://www.ncbi.nlm.nih.gov/pubmed/11045626  (casein as a stimulator acting on Lon)
decided to add paper link  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2144696/
http://www.ncbi.nlm.nih.gov/pubmed/10734549
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC216189/ 
http://www.ncbi.nlm.nih.gov/pubmed/3042779 (sequence)

In E.coli does gluten based on a similar sequence do the same thing?

2. sutterella
Lon and other Bacterias
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492299/
Can we find Lon in Sutterella which the the bacteria associated with autism?
Sutterella does have a long form.

3. Fungal infections
In Candida which can change morphology, mold to yeast, is the LON enzyme involved ?
Here are papers where compounds appear to effect the morphology of fungus:
REF to come?

Lon and Mdj1 sequences are homologous among dimorphic fungi
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1405898/
http://www.ncbi.nlm.nih.gov/pubmed/11447604

Paracoccidioides brasiliensis where LON seems to be involved with the dimorphic switching between mold and yeast when the temperature changes
http://www.ncbi.nlm.nih.gov/pubmed/17166750

In Candida does a sequence in corn gluten act like gluten and casein on LON?
Ref
http://www.ncbi.nlm.nih.gov/pubmed/22693589

some strains of candida change morphology with temperature
http://www.ncbi.nlm.nih.gov/pubmed/6998950

4.Mycobacteria
Mycobacterias and LON (they must change morphology too....and will be gluten and casein sensitive)
http://www.ncbi.nlm.nih.gov/pubmed/9425059
http://www.ncbi.nlm.nih.gov/pubmed/11045626 (casein acting on a mycobacteria Lon)

There are rough and smooth morphologies for mycobacteria.
http://www.ncbi.nlm.nih.gov/pubmed/13894939?dopt=Abstract&holding=f1000,f1000m,isrctn

Useful INFO:
hmm....Lon differences?  http://www.ncbi.nlm.nih.gov/pubmed/22119779 
PinA inhibits only the protease binding site http://jb.asm.org/content/170/7/3016.full.pdf
note that Lon was the first atp-dependent protease discovered 

 I need to find the stimulating sequence of casein that acts on Lon and see if it matches gluten...what i have stumbled across seems to have brought me back to where i started. (not the protease site)

I had read about organic crab grass prevention using corn gluten by ohio state.
Corn gluten haults the roots of grass seed from forming....here now... I found a paper where in plants Lon mutations hurt shoots and roots: http://www.ncbi.nlm.nih.gov/pubmed/22968828

Can anyone out there follow my logic?