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Prions In the News (Unfortunately)

Let’s talk about proteins for a few minutes – nasty, unfriendly proteins, of the sort that will ball up and crash out of solution the first chance they get. Anyone working in a protein purification lab will have encountered plenty of these, and will be familiar with the various tricks available to keep things in solution and off the bottom of the tube. But what about when this starts happening in a living system?

That’s the situation, of course, in a number of diseases – Alzheimer’s, Parkinson’s, ALS, CJD and many more (here’s a list just for amyloid proteins alone). And while there’s some room for cause-and-effect arguing in some of these, in others it seems clear that the primary event is protein aggregation. It’s a constant problem, as those folks expressing and purifying proteins in the lab will tell you, and it’s a constant problem in the cell as well. The beta-sheet structure is a key protein folding motif, but it can get out of hand. When things get out of hand (as they do in this structure, blogged about here recently), beta-sheet regions can start slapping onto each other like a stack of two-sided Velco pads. (In fact, you’d have to figure that there’s been evolutionary pressure away from such sequences and other crash-out-in-a-heap motifs).

The most dramatic (and unnerving) of the protein aggregation diseases are those caused by prions, which are proteins that can catalyze infectious misfolding. Stanley Prusiner got what was (at the time) a fairly controversial Nobel prize for his work in this field, but time has vindicated him. And he and his co-workers have just identified a new prion disease (the first in many years). The rare condition known as multiple system atrophy now appears to be caused by a prion version of alpha-synuclein, the same protein involved in Parkinson’s. (Whether Parkinson’s itself is caused (or at least exacerbated) by prions remains an open question).

And coincidentally, there is a new paper in Nature that reports transmissible beta-amyloid pathology in humans. The authors were studying tissue from patients who had died from iatrogenic CJD, bought on by cadaver-derived growth hormone treatment. That mode of therapy came to a gravel-spraying halt in about 1985, when the dangers of prion transmission had become clear, but the latency time is so terrifyingly long and unpredictable that people are still manifesting with the disease. Histopathology showed the presence of amyloid deposits in the gray matter and blood vessels, not associated with the CJD protein deposits. These are not seen in other patients who have had growth hormone therapy from other sources, not seen in another cohort of patients with other prion conditions, and none of these eight patients had any of the known genetic predispositions to amyloid deposition. The hypothesis is that these represent a transmissable amyloid pathology, which has never until now been demonstrated in humans (the most direct experiments to do so being ruled out for obvious reasons!) Animal models have shown that it’s possible, though.

This immediately suggests several things that have to be looked into: for one thing, can other patients be at risk of having amyloid pathology transmitted to them by surgical or medical procedures? Prion proteins, worryingly, are known to adhere to metal surfaces and to be resistant to many standard methods of cleaning and sterilization. Another larger question is whether amyloid diseases (including Alzheimer’s) have an infectious component in the general population. This paper certainly doesn’t prove that they do, of course, and there’s a lot of epidemiology (blood transfusion data and more) to suggest that Alzheimer’s, at least, is not spread in this way. But it does put the idea back on the table, to some extent, and since there’s less information on the potential transmissibility of the less common amyloid diseases, this is something that’s going to have to be looked into as well.

So what does one do about a prion disease? At the moment, the standard medical treatment is. . .nothing, basically. One of the most disturbing features of something like CJD is that we have no weapons against it at all. A lot of work has gone into trying to find agents that will interrupt the protein-folding cascade, but it’s a tall order. Protein aggregation tends to be a thermodynamic tar pit, and keeping things from sliding off into it is not easy. A number of aminothiazole compounds have shown efficacy in animal models of prion diseases, though, but (just to make things trickier) drug-resistant prions have been shown to develop under these conditions as well. If you’re looking for a major unsolved therapeutic problem, look no further.

 

49 comments on “Prions In the News (Unfortunately)”

  1. db says:

    Derek,

    What’s with the random strikethroughs of hyperlinks? I’ve noticed this in a lot of your posts, and even in a number of posts brought along from the Corante days.

    There seem to be too many of them for you to be using this as a device to show contradiction (as some people do) or as corrections.

    1. anon says:

      Looking at the HTML source, it looks like there’s a “class = broken_link” attribute on all of the affected links, and elsewhere there’s a bit of CSS specifying a “line-through” decoration for text with this class. I’m guessing Derek is using the WordPress plug-in “Broken Link Checker” (or some similar tool) to detect and tag broken links automatically. (And it’s not doing its job very well, since all of those links work.)

  2. Ash (Wavefunction) says:

    Just a historical note: One of the best (and scariest) book on the history of prion diseases is Richard Rhodes’s “Deadly Feasts”. In fact Rhodes wrote a skeptical profile of Prusiner in the New Yorker right when the Nobel Prize was announced, and Prusiner did not make it any easier by announcing in the 1980s that he would no longer talk to journalists after one of them had drawn an unflattering portrait of him in an article earlier.

  3. Hap says:

    I liked that book, but I think it went out of print and my library doesn’t have it now. I wondered though why most of the scary stuff in it (particularly about the likely or possible propagation of prion diseases) hasn’t happened. It seemed somewhat analogous to biological weapons, in that there seems to be lots of potential for something really bad, but it hasn’t happened (yet) – did we get lucky, or is there some reason why they haven’t done what (at least some people) thought they would?

    I think the strikethoughs are supposed to be underlines that the font puts too high so that they look like strikethroughs.

    1. The Aqueous Layer says:

      @Hap

      Amazon has plenty of copies of that book at a reasonable price, new and used….

  4. Kelvin says:

    This is hardly surprising as all amyloid structures are composed of beta-sheets that have a natural propensity to propagate, hence how they aggregate in the first place. In fact seeding and aggregation are part of the same process.

    Anyhow this reminds me of my work as a post-doc and later as founder of Senexis, where we designed and developed generic amyloid inhibitors based on N-methylated versions of the target amyloid peptide itself. The idea was that putting an N-methyl group on every other residue would block only one edge of the peptide backbone while keeping the other edge sticky so that it would bind to the target peptide. These inhibitors were extremely potent (1 nM), resistant to proteolysis, highly soluble (despite their hydrophobicity) and also wizzed through cell membranes. Unfortunately the technology and company were ultimately killed when the CEO (ex-Pfizer) and investors suddenly decided that it couldn’t work. Shame we never got round to actually testing it properly!

  5. Lane Simonian says:

    I like the caution taken in this blog. Alzheimer’s disease is probably not a prion disease and it probably is not infectious.

    The overlapping paths create confusion and misinterpretations. Phospholipase C leads to the release of the non-infectious prion protein from phospholipids. Through protein kinase, phospholipase C leads to the production of peroxynitrites, and caspases–the latter of which activates the beta secretase which results in the amyloid precursor protein. Phospholipase C via inositol triphosphate leads to the release of intracellular calcium which can result in the release of intracellular calcium which activates calpains–the enzyme which activates the gamma secretase and results in the formation of amyloid oligomers.

    The next step is tyrosine nitration which often leads to misfolded proteins (amyloid plaques, infectious prion proteins, tau proteins, etc.). Nitration can be mediated by peroxynitrites and/or via copper ions.

    http://www.ncbi.nlm.nih.gov/pubmed/14713301

    The nitration of oligomers into plaques unlike the nitration of prion proteins and tau proteins is likely a protective measure (From: Amyloid Deposits: Protection Against Toxic Protein Species?. Therefore, PrPres would appear to be rendered nonpathogenic by its sequestration in amyloid plaques). The formation of amyloid plaques may stop Alzheimer’s disease from becoming a prion disease. By absorbing zinc and copper, plaques also stop the production of hydrogen peroxide and slow down tyrosine nitration, but the disease continues via the overactivation of NMDA receptors via peroxynitrite mediated nitration.

  6. Anon says:

    Just a random question: Can I use AdBlocker to filter out anything with the word peroxynitrites in it?

  7. d says:

    One thing to note from the MSA paper is that it only seems to be transmissible to other mice that are homozygous for the A53T mutation. An interesting hallmark of prion disease (pathogenic PrPSc) seems to be it’s ability to cross ‘prion species barriers’, in other words it can still be transmissible from mutant forms to wild-type and even across species in some cases. The MSA even seems to necessitate the mutated form of synuclein for pathogenicity. While worrying, is probably a bit more rare and not quiet the same as other prion diseases.

    The AD story I find to be much more troubling. Perhaps tangled tau and Abeta are not transmissible via blood transfusion alone, and they require a vessel to cross the BBB – like PrP as a carrier. Are there other proteins that may shuttle pathogenic AD-related proteins into the brain? Perhaps metals or other chemicals? As noted, there were no risk factors for AD in these patients and many labs have shown that tau (at least) can act as a prion in vitro and in animal models, even when mutations are present (P301L/S being the classic mutations that can still seed WT and other variants). People have speculated on the prion-like nature of Tau/Abeta and other proteins for some time now, it will be interesting to see where this research goes.

  8. Dave says:

    How can any discussion of prion diseases not mention Kuru?

    https://en.wikipedia.org/wiki/Kuru_%28disease%29

    Dave

  9. MTK says:

    Stupid question: How is the word prion pronounced?

    I’ve always said pree-on, but I recently heard someone say pry-on and it got me wondering if one is correct or if both pronunciations are used.

  10. Paul Brookes says:

    Meh. Call me a skeptic when it comes to prions. They’re an interesting set of proteins, but the attractiveness of labeling certain diseases as transmissible has led to a lot of hype that the underlying data does not appear to strongly support.

    It might have something to do with the numerous problems in the papers of Claudio Soto that have been pointed out online, including at PubPeer (https://pubpeer.com/search?q=claudio+soto). There are several examples of apparent re-use of blots and images surrounding the PMCA method, which is critical to the detection of prion proteins in biological isolates. One has to ask, if PMCA is such a “robust” method, why isn’t it used as a diagnostic test in clinical labs all over the world? It’s been around for over a decade but the uptake has been slow, which could suggest reproducibility issues.

    Back in the day when I had a blog on such matters, numerous papers on prions were highlighted for apparent data irregularities, including from prominent labs in the field… Stanley Prusiner, Bradley Hyman, Claudio Hetz, David Westaway, Maria Gassett, Edward Hoover, Giovanna Malucci. Some have been corrected or retracted (per Retraction Watch), but many of these papers continue to be cited and remain uncorrected despite journals being notified several years ago.

    Until the prion field as a whole does a better job of cleaning up the noise surrounding core methodologies, a healthy degree of skepticism is required in evaluating bold claims of transmissible neurodegeneration.

  11. Lane Simonian says:

    From the link above:

    Cu2+ (in the form of CuSO4) treatment of synaptosomes triggered a milder oxidative effect leading to a bell-shaped increase of PrPrec binding to synaptosomal components, counteracted by the natural thiol agents, glutathione and thioredoxin

    Nearly every neurodegenerative disease is an oxidative stress related disease. That stress may be due to genes, environmental contaminants, or an unhealthy diet and it may lead to misfolded proteins. Moreover to the extent that misfolded proteins contribute to further oxidation this can potentially be dealt with by using the appropriate antioxidants.

    For Alzheimer’s disease see the following recent study:

    http://www.medicaldaily.com/resveratrol-compound-red-wine-may-slow-alzheimers-disease-progression-352594

    And resveratrol is not even the best antioxidant for treating Alzheimer’s disease.

  12. Smoki says:

    Regarding the problems of PMCA …. yes, I completely agree that it is highly problmatic. But most of the foundation work was done before PMCA was even developed.

    I think there is no doubt that these diseases are transmissible, and I find this alone makes the field really remarkable.

  13. johnnyboy says:

    @ MTK: I’m sure you can pronounce it whichever way you want, but Prusiner himself pronounces it “pree-on”.

  14. johnnyboy says:

    And regarding transmissibility: Technical issues with specific papers aside, I don’t think there is no longer any reasonable doubt about transmissibility of kuru (man to man), nvCJD (cow to man), and BSE (cow to cow, and probably sheep to cow).

  15. Anon@11:26 am — sadly I don’t think you can configure AdBlock to filter out individual blog comments based on text matching, but if you don’t mind doing a little source spelunking it should be relatively straightforward to put together a greasemonkey script to make Lane’s contributions vanish. Look for divs with class=”comment-body” and some obvious text to match inside, and you should be able to fold them up.

  16. Lane Simonian says:

    For those who wish to put things together (all others simply ignore):

    Abstract In this study, we explored the role of ferulic acid on prion replication by established scrapie-infected mouse neuroblastoma cells (ScN2a). Western blot analysis of PK-digested PrP(Sc) revealed the role of ferulic acid on prion replication. The results showed that 0.5, 1 and 5 g/mL of ferulic acid could significantly inhibit PrPSc formation (P<0.01). Ferulic acid, a Chinese medicine monomer, could inhibit PrPSc replication. We conclude that ferulic acid may play a role in the treatment of prion diseases, which provides a new idea for the treatment of prion in the future.

    To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

    Results: The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up. Discussion These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

    Results: Treatment with Feru-guard [ferulic acid in rice bran oil and Angelica archangelica] led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data.

    CONCLUSION:
    Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

  17. Mark Thorson says:

    Lane, you are a crank.

  18. Nick K says:

    If aggregated proteins represent a thermodynamic sink, why do they need a prion and don’t merely aggregate spontaneously?

  19. Kelvin says:

    @Nick K: Good Question. Answer: Because of the kinetic barrier (loss of entropy) required to make an otherwise floppy peptide join an ordered structure. But once it joins, the release of water from the peptide surface more than makes up for the loss in entropy.

  20. Kelvin says:

    PS. I should clarify that seeding, where two floppy peptides join each other to form an ordered structure has an even higher kinetic barrier than one floppy peptide joining an existing ordered amyloid seed. Just think of the probabilities involved of two floppy peptides being in the right ordered conformation, proximity and orientation at the same time. It’s no wonder that seeding is more unlikely than continued aggregation, but once it happens…

  21. Nick K says:

    @Kelvin: So it’s a bit like a supersaturated solution needing a seed crystal to start crystallization? The proteins are metastable in non-aggregated form?

  22. Kelvin says:

    Exactly the same principle. The only difference is that the energies involved (both kinetic barrier and thermodynamic stability of the aggregated end-state) are much greater than with most simple inorganic crystals because the molecules are bigger and so the intermolecular interactions are much greater.

  23. Dan says:

    Could surgical instruments simply be cleaned with biological washing powder? Or are prions resistant to proteases? If it works, Persil should hurry up and file a new use patent…

  24. Kelvin says:

    … and the only way to stop aggregation is to either:

    1. Increase the kinetic barrier by stabilizing the unaggregated form in another (non-beta strand) conformation.
    2. Effectively compete with the aggregation process with an inhibitor that binds more strongly to the aggregated peptide than than the peptide binds to itself. This was the strategy we used with the N-methylated peptides I described earlier, where the N-methyl groups actually favour the beta-strand conformation, but block further association.

  25. Kelvin says:

    @Dan: aggregated prions are highly resistant to virtually everything, except maybe burning. Even chemical hydrolysis with NaOH is not very effective as it is so tightly packed.

  26. Anonymous BMS Researcher says:

    Here’s the 1985 case report entitled “Fatal Degenerative Neurologic Disease in Patients Who Received Pituitary-Derived Human Growth Hormone”
    http://www.cdc.gov/mmwr/preview/mmwrhtml/00000563.htm

  27. Nick K says:

    @Kelvin: It’s a rather alarming thought that only an entropic barrier is preventing my brain proteins from aggregating….

  28. Kelvin says:

    PS. Nick K: Another way to think of it is like boiling an egg, which also involves protein aggregation…

    A raw egg is a meta-stable form of a boiled egg. It takes energy to boil an egg due to the kinetic barrier, but once boiled you will never be able to unboil it.

  29. Kelvin says:

    … so don’t boil your brain! 🙂

  30. dearieme says:

    “once boiled you will never be able to unboil it”. To unboil an egg you feed it to a chicken. Ditto to unomelette.

  31. Kelvin says:

    ^ Funny! 🙂

    Actually, it is possible to “unboil” an egg, but not with heat alone. You have to add plenty of:

    1) Chemical denaturant (e.g., guanidine HCl) to break up the hydrogen bonds between peptide backbones;
    2) Detergent to break up the hydrophobic interactions between peptide side chains; AND
    3) Reducing agent (e.g., mercaptoethanol) to break the disulphide bridges between cystine residues

    Then technically you can gradually dialyze out these reagents to refold the proteins back into their original forms, then reconcentrate the solution to get your raw egg!

  32. Hi,
    talking about AD being infectious is just totally misleading and incorrect. There is absolutely not evidence that is true firstly because there is no concrete evidence that amyloids cause AD (there certainly are reports suggesting that). And secondly, given taht most cases are sporadic, how does one reconcile as I am sure not all these patients are getting blood transfusions for transmission of prions. And finally, can Abeta form prions? The data is just too dubious to make any of those claims and it just adds more noise than weight into the mechanistic details of how AD initiates or propagates.

    Best,
    Neeraj

  33. Kelvin says:

    @Neeraj: I have no doubt that amyloid transferred from the brain of an AD patient could help seed amyloid formation in a healthy person, but unless you’re getting a brain transplant it’s rather academic, since transfer from one brain to another is otherwise highly unlikely (even through blood transfusion) while as you say, the link between amyloid and AD is not proven, and the specific form of amyloid transferred may not be relevant in any case.

  34. Dan says:

    @Kelvin: If prions are so very resistant, shouldn’t all of nature have turned to prions by now?! And, in other news: BOILED EGGS LINKED TO CJD!

  35. Lane Simonian says:

    I liked the way they used crank in this sentence:

    “when he first started to air his views, they labeled him a crank”

    It is all about labeling, evidence by damned.

    Having said that, let us look at the evidence again. Tyrosine nitration is what both transforms proteins and makes them resistant to proteases.

    Post-translational modifications in prion proteins.

    http://www.ncbi.nlm.nih.gov/pubmed/12470218

    Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.

    Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation.

    The first two are problems. Nitrated prions further contribute to oxidative stress and nitrated tau proteins interfere with neurotransmissions and the transport of nutrients in the brain. Nitration of amyloid, on the other hand, may sequester potentially infectious prion proteins.

    When hydrogen peroxide and peroxyntrites are scavenged they produce water and water is putative de-nitrating agent for tyrosine. So not only do antioxidants limit the nitration of tyrosine, they also contribute to its de-nitration and proteolysis.

    Denitration of peroxynitrite-treated proteins by ‘protein nitratases’ from rat brain and heart.

    Protein-Tyr-NO2 + H2O –> Protein-Tyr-H + H+ + NO3-. The nitration/denitration of protein-tyrosine may be crucial in regulating signal transduction.

    Back for just a second to ferulic acid:

    Peroxynitrite is a cytotoxic species generated by the reaction between superoxide and nitric oxide. In this study the ability of hydroxycinnamate antioxidants to decrease peroxynitrite-mediated nitration of tyrosine was investigated. The results obtained show that all compounds were able to inhibit nitration of tyrosine. The potency of inhibitory activity was in the order; caffeic acid > or = chlorogenic acid > or = ferulic acid > p-coumaric acid > ocoumaric acid > m-coumaric acid.

    Tyrosine nitration of various proteins plays a role in a great variety of neurodegenerative disease–prevent and reverse that nitration and the possibility to effectively treat at least some of these disease exists.

  36. Kelvin says:

    @Dan: Well no, because they are still degraded eventually (e.g., by bacterial decomposition and/or oxidation), albeit very slowly. Just like the world isn’t full of boiled eggs.

  37. Kelvin says:

    … or hair, which is another very resistant form of aggregated protein, for example.

  38. Lane Simonian says:

    Just one more study:

    Oxidative stress has been shown to be important in several neurodegenerative disorders. Previous in vitro studies have already demonstrated the ability of a prion protein fragment to induce oxidative stress in cultured cells. By immunohistochemistry for nitrotyrosine (NT) and heme oxygenase-1 as markers for oxidative stress, we found widespread neuronal labeling for NT in scrapie-infected mouse brains, in agreement with peroxynitrite mediated neuronal degeneration. Damage by free radicals is a likely cause for neurodegeneration in prion disease, and antioxidants are a potential therapy of these disorders.

    The challenge for medicinal chemists is find a way to deliver more of the most effective antioxidants to the brain. To a certain extent this is already being done, but unfortunately too much attention has been paid to the misfolded proteins themselves and not enough on how to prevent or reverse oxidative damage.

  39. Claudiu Bandea says:

    Here is an alternative take on ‘prions’ and ‘protein misfolding diseases’, including AD, PD and ALS: http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

  40. Paul Brookes says:

    @Lane Simonian, with all due respect, your terminology is sloppy in a few areas. Here are a couple of examples….

    (1) “Peroxynitrites”. Why the plural? There’s a molecule called peroxynitrite (ONOO-), aka peroxynitrous acid (ONOOH) and it’s one molecule. There are not a family of these things. It’s one species, that’s all. FYI, yes ONOO- can be made by direct reaction of superoxide and nitric oxide, but the chances of this occurring in vivo are very very low indeed (see early work of Radi & Freeman). There are other routes to tyrosine nitration such as MPO catalysed, using nitrite (NO2-). The notion of peroxynitrite as a biologically significant source of 3-N-Tyr is about a decade out of date.

    (2) “Oxidative stress has been shown to be important in several neurodegenerative disorders”. No, it’s been associated with. That’s not cause-and-effect. Lots of diseases are associated with oxidative stress. That’s a different thing altogether from proving that Ox-stress actually contributes to disease pathology or progression. If it were so simple, then antioxidants would be in the clinic, but we all know from expensive experience they are D.O.A. as drugs.

    (3) Bringing these 2 thoughts together, there’s a large assumption that tyrosine nitration is biologically relevant. Again, looking back into the older literature one can find big lists of proteins that CAN be nitrated (e.g. by throwing ONOOH onto cells). That’s very different from the nitration event being causative in the change of function in a disease setting. For peroxynitrite as a biological oxidant, by the time it gets around to nitrating a tyrosine, all of the cysteines and methionines in that protein will be shot to hell (there’s an argument that in some cases they might be “sacrificial”, to protect the Tyr residue). So yes, we can measure 3-N-Tyr and associate it with altered function of a protein, but it’s very difficult to prove that the altered function is caused by the nitration, given so much else going on with Cys and Met residues in the same protein. There are VERY few examples in which N-Tyr has proven to be a causative post-translational modification.

    Bottom line – just ‘cos we can measure it, doesn’t mean it has any role in the biology.

  41. Anon says:

    @Paul

    You are wasting your time. Lane is already convinced and adamant that rose oil or whatever is the cure-all for AD, based on his n=1, non-blinded, non-randomized study with his mother. All the rest of the “scientific” shite he regurgitates is just cherry-picked copy-pasted noise to justify his faith.

  42. Anon says:

    @Paul

    You are wasting your time. Lane is already convinced and adamant that rose oil or whatever is the cure-all for AD, based on his n=1, non-blinded, non-placebo-controlled, non-randomized study with his own mother. All the rest of the “scientific” shite he regurgitates is just cherry-picked copy-pasted noise to justify his faith.

  43. lane simonian says:

    The first part of point number one is rather trivial. Yes, there is only one compound called peroxynitrite (ONOO-) that can become an acid (peroxnitrous acid). But not just one peroxynitrite is produced in the body. Example: there is only one animal called a cat but when you have more than one cat you call them cats. It is not science just grammar.

    The next point is more important. Yes there are other routes to tyrosine nitration rather than peroxynitrites, including via transition metals. Many peroxynitrite scavengers are also metal chelators, so one compound may inhibit nitration by more than one route. In the case of myleperoxidase, it is involved in the scavenging of peroxynitrites which produces nitrite (NO2-) and water. Hydrogen peroxide (which is produced early in Alzheimer’s disease) can recombine with nitrite to produce peroxynitrites, so myleperoxidase (unlike transtion metals) may not be a peroxynitrite independent route to tyrosine nitration.

    Myeloperoxidase scavenges peroxynitrite: A novel anti-inflammatory action of the heme enzyme.

    The idea that peroxynitrites do not play a significant role in a variety of disease is refuted by a wealth of evidence including some by Radi himself who was a pioneer in the field.

    http://www.enzim.hu/~lbarna/articles/17667957.pdf

    Nitric oxide and peroxynitrite in health and disease.

    On point number two, peroxynitrites have been “tied” by various researchers to a variety of damage in Alzheimer’s disease including lipid peroxidation, inflammation, mitochondrial dysfunction, cysteine oxidation, tyrosine nitration, DNA damage, and apoptosis (see KEGG pathway for Alzheimer’s disease; although perhaps to your point it does leave out tyrosine nitration).

    On point number three, various scientists will disagree with you.

    Role of protein tyrosine nitration in neurodegenerative diseases and atherosclerosis.

    If there is some order for protein nitration, I would be interested in seeing it.

    I complement you on this; at least you are trying to argue science with me (even if it is a somewhat condescending fashion). Most people just throw out insults which is a bit lazy and does not advance anything (except for allowing people to relieve some of their stress).

    The argument that oxidation is the primary cause of Alzheimer’s disease and that specific antioxidants can be used to treat it (methoxyphenols which are highly efficient hydrogen donors and peroxynitrite scavengers) is based on several clinical trials, multiple case studies, and dozens of articles. I may still be wrong, but if I am I am in very good company.

  44. Kelvin says:

    Interesting coincidence following my earlier comments about unboiling an egg:

    Here is the full list of Ig Nobel prize winners:
    Chemistry – Callum Ormonde (University of Western Australia) and colleagues, for inventing a chemical recipe to partially un-boil an egg.

    http://www.bbc.com/news/science-environment-34278595

  45. Lane Simonian says:

    The idea that peroxynitrite-mediated tyrosine nitration contributes to various neurological disease is still very much alive and well.

    PP50 – Polyphenols protect against SIN-1 induced nitration of cellular proteins

    Peroxynitrite anion (ONOO-) is a potent oxidizing and nitrating agent. A primary effect of ONOO- on proteins is nitration of tyrosine residues. Nitration of tyrosine residues has been implicated in the pathophysiology of various, particularly neurodegenerative, disorders and aging, therefore search for agents preventing or limiting protein modifications by peroxynitrite is of interest. Our previous study has identified compounds, mostly polyphenols, the most reactive with peroxynitrite…The sequence of effectivity in protection against nitration of intracellular proteins was as follows: ferulic acid > uric acid > desferrioxamine > naringin hydrate > luteolin > genistein > quercetin. This sequence is different from that found in a cell-free system of tyrosine nitration, confirming that other factors, apart from reactivity with peroxynitrite alone, related to the cellular behavior of antioxidants, are important for their protective efficiency against nitration in situ.

    In this light, the above results for ferulic acid in terms of treating various neurological disease and the finding that gout (caused by high levels of uric acid) reduces the risk for Alzheimer’s disease make perfect sense.

    http://www.ncbi.nlm.nih.gov/pubmedhealth/behindtheheadlines/news/2015-03-05-people-with-gout-have-lower-risk-of-alzheimers-disease-/

    The resistance to the idea that oxidants not amyoid nor tau tangles cause Alzheimer’s disease is rather fierce, but it is getting increasingly difficult to maintain the latter.

  46. ProfessorPlum says:

    Prions are some of the scariest substances I’ve ever studied. They were all the rage during my time at UCSF. They are kind of like Vonnegut’s Ice-Nine – once you are in that thermodynamic hole, there is (seemingly) no getting out.

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