Parkinsons-Like Neurodegenerative Disease Linked to Prion | Hacker News Reader

Parkinsons-Like Neurodegenerative Disease Linked to Prion

cen.acs.org

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I gave to the Michael J Fox foundation last year so I'm on their mailing list.

https://www.michaeljfox.org/

There seems to be a lot of research and progress into the disease. Andy Grove of Intel has been fighting the disease.

http://www.forbes.com/forbes/2008/0128/070.html

We've been fighting diseases like these for a while. It would be nice to get a few more wins.

There is no conventional treatment for prion disease, but methylene blue (Methylthioninium chloride), which has been around for over 100 years, has been investigated as a preventive treatment with some success in mouse models:

http://www.ncbi.nlm.nih.gov/pubmed/23022479

http://www.ncbi.nlm.nih.gov/pubmed/25958115

The problem is is that it's not patentable and it's super cheap. Thus, various drug companies like TauRX are tweaking it a little so it's patentable and are currently trying to get it through clinical trials.

http://taurx.com/science

What's really interesting is the nootropic crowd has been experimenting with methylene blue for years; a lot of stacks published by nootropic enthusiasts have featured it to increase ATP production (same reason why I take methylcobalamin for my B12).

I personally suspect a lot of "modern" neurodegeneration diseases (such as Alzheimer's) are directly linked to malfunction and eventual death of mitochondria through years of abuse by poor dietary standards, especially in the US, as in, not enough of the B vitamins (which participates in the production of ATP, CoA, acetyl-CoA, NAD, NADP, etc), including Choline and PABA (not usually considered B Vitamins, but have, at one point, been assigned B numbers).

maybe, but the BS detector of a lot of people in the field are ticked off when someone tries to propose one cause for a broad variety of biologically different disease. It's also hard to prove that it isn't a general effect, vs the cause, of badness. mitochondrially-powered eukaryotic cells are awfully more susceptible to many things and my cynicism suspects you can measure worn/beaten up mitochondria in pretty much anyone as they age. The last CoQ10 trial that was based on the mitochondrial stuff for Parkinson's failed miserably.

If someone can design an experiment to prove a causative role of mitochondria in all of this, more power to them, but a lot of the proposed mechanisms never really appealed to me as all that compelling, other than to note correlation, i.e. "All of our Disease X patients exhibits abnormal test Y, which could potentially, possibly, but not definitely, be related to mitochondrial dysfunction, and this is why the NIH should give our group more grant money next year!"

I don't understand the point of supplementing CoQ10 alone. CoQ10 is one of about twenty or thirty things that should be supplemented if, indeed, this is the correct route to improving life.

IMHO, it was the easy way out. You do a trial with one substance at a time, and do a simple randomized controlled trial; which is how most of medical research works. More than one agent and you have to hire more statisticians to do your experimental design, and it is harder to get somewhat simpleminded grant committees to understand your proposal.

Methylene blue improves Complex IV function in mitochondria, so it certainly has a direct effect on mitochondrial function. It's actually used as an antidote to several poisons that inhibit mitochondrial function[1].

[1] https://en.wikipedia.org/wiki/Methylene_blue

Methylene blue is available in hospitals, often as a vasopressor of last resort ("four pressor shock").

I found prions to be the most fascinating thing in my biology classes. And the fact that we still don't know that much about them bemuses me. The debate section from the Wikipedia is worth reading [0] due to the fact that we still don't know "Whether prions cause disease or are merely a symptom caused by a different agent is still debated by a minority of researchers".

[0] https://en.wikipedia.org/wiki/Prion#Debate

I think that debate is mostly being waged by people who don't want to accept that our existing models of disease are woefully simplistic. I find it mainly amusing because the previous battle similar to this was from people who thought nucleic acids couldn't be coding molecules while proteins could!

I was at UCSF when Prusiner was doing some of his best work on prions- it typically involved infecting mice and waiting 2 months to get a result that could be analyzed molecularly.

Anyway, this model system: https://en.wikipedia.org/wiki/Fungal_prion is pretty well understood, and it's generally hoped that understanding its molecular behavior will go a long way to understanding mammalian prions.

To be honest, it may all be semantics. Does synuclein aggregate? for sure. Do they self aggregate? probably. Are they "prions"? That I'm not sure, as they are probably molecularly quite different than say CJD or GSS proteins. But "prions" is a scientifically flashy term, tied not at least in small part to Prusiner's personality (and of Olanow, who I'm sure is helping stir up the pot a little bit), and gets a lot of buzz.

I think the effort and the debate are worth it though because on the top of it all, prion or not, the root cause of Parkinson's disease is still not known. At least several million bucks of taxpayer money will probably go to prion-related grants because of the publicity and interested of various research groups, and while the prion idea may pan out or not, it can only add to the effort to figure out how this all starts in the body.

> I find it mainly amusing because the previous battle similar to this was from people who thought nucleic acids couldn't be coding molecules while proteins could!

Did you mean s/be coding molecules/have catalytic function/ ?

No, although that was another interesting battle.

I'm referring to the determination that DNA, not protein, was the hereditary molecule. I probably just worded this poorly, to give the implication that coding capability was limited to proteins. It's just that most people at the time thought that DNA was found in either nA (a string of As), nT, nG, or nC, or random arrangements. More than anything people just didn't think that DNA could "code" for anything, while proteins could, because people didn't seem to realize that unique sequences of heteropolymers was a valid form of coding. It was mostly thought that the information was stored in huge structures formed by proteins, and that the coding information was architectural.

See Mayr, "Origin of Biological Thought", final chapter, starting with the section on Meischer. Or Crick's "On Protein Synthesis" where he proposed the linear code: http://profiles.nlm.nih.gov/ps/access/scbbzy.pdf

I'm reminded being scoffed at: "It's not contagious."

I don't mean to be part of a panic, but there's been a lot of "it isn't" based not on science but on, frankly, opinion.

Nowadays they think that they can link something like 25 - 30 % of cancers to viral infections. (I seem to recall 25 being more current, with 30 being expected soon.)

In a broader context, sooner or later we will have to re-evaluate things like OCD. (I'm thinking of the hand washing and "cleanliness" aspects, currently.) They may not be "merely" a disease or disfunction, but rather an extremity on yet another "spectrum", one that may in some circumstances actually provide an advantage. Perhaps explaining its continued occurrence.

Prions are new to our understanding. Except, as we continue to look at long-standing human behaviors, now with knowledge of them, we may find that, indirectly, they are not entirely new to our understanding and behaviors.

(Nonetheless, I agree with others here and in general: Scary stuff.)

P.S. I wonder whether/when we will discover any advantageous aspects to some of them, or at least benign.

While the cause remains unknown there's research showing that OCD may in part be triggered by infection: http://www.nimh.nih.gov/health/publications/pandas/index.sht...

Maybe but people look at epidemiologic patterns (i.e. the whole point of the World of Warcraft Zombie paper earlier), and Parkinson's disease doesn't really seem to show any of the typical patterns. It's a really difficult problem, and also the reportability of linked cases may be an issue, as if you "get" parkinson's, you don't really know until 10 years or more after the fact...

There may be something to whatever makes misfolded synucleins agregate, but at the last big international conference, there was a battle royale between the pro's and the con's of prionism, i.e. do synucleins exhibit the properties of the prions involved in CJD and other prion disease, vs. just being an example of a self aggregating protein. The con's won by a healthy margin

Prions are scary, for the reason that "all known prion diseases...are untreatable and fatal." How do you stop a prion? For that matter, how do you stop anything in the brain (without cutting it out)?

Prions are indeed scary - I still remember a comment to the effect that pathologists can never be really sure their instruments are safe to work with again.

( http://pipeline.corante.com/archives/2011/11/29/a_things_i_w... )

A bit more about that from a better source: http://www.scientificamerican.com/article/surgical-exposure-...

A couple of months after having surgery to replace a blown cervical disk, I received a letter telling me that a prior surgical patient had died of Creutzfeldt–Jakob and, among other things, that I may have been exposed via surgical instruments.

My girlfriend at the time was actually really knowledgeable about Creutzfeldt–Jakob. After many, many questions and a some more research on my own, the one consoling thing is that if I had it, by the time the symptoms manifested, I would be too incoherent to really understand what was happening.

While I've certainly lost some cognitive abilities in the intervening decade, I haven't had any symptoms of Creutzfeldt-Jakob. However, I have felt compelled to stop donating blood, and have rescinded my organ-donor status (although I've made it clear to my family members that my body is to me made available for research purposes).

edited: for clarity

Wow, what a scary realization that our once-thought-safe sterilization techniques were inadequate.

This article is a bit more optimistic that a combination of screening and better sterilization techniques has reduced the risk to more acceptable levels: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358170/

"Fragile instruments such as endoscopes and electrodes remain a challenge, but new and gentler methods— alkaline cleaning solutions, phenolics, and gaseous hydrogen peroxide—have proven harmless to instruments and give a high, if not always complete, degree of prion inactivation (24–26)."

"I still remember a comment to the effect that pathologists can never be really sure their instruments are safe to work with again."

That sounds like an easy (albeit wasteful) problem to solve.

Stroke ( ischemic or hemorrhagic) can be fixed with mini invasive surgery. Neuro surgeons insert "tools" through your vascular system (inside the leg or neck) and get some feedback with X ray imaging. For plumbing issues, it works great in the first few hours.

re: your comment 'how do you stop anything in the brain - cut the brain out ?'

No, you can still design chemicals and peptides that could cross the blood brain barrier via adsorptive endocytosis, saturable transporters and trans-membrane diffusion.

Drug Delivery to the Brain: https://en.wikipedia.org/wiki/Drug_delivery_to_the_brain

Modes of Transport: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697631/

So the idea that neurodegeneration is essential a manifestation of protein-specific prion disease is not a new idea[1][2][3][4][5] but is one which is steadily gaining traction. That said, from a complexity perspective we're still at the tip of the iceberg.

There's extensive evidence to suggest that the big, fiber-like aggregates that form in these diseases may in fact be neuroprotective, and represent a largely inert thermodynamic end state (basically a big inert crystal which kind of hangs out but doesn't do much damage). More labile, smaller aggregates (basically blobs of protein stuck together) which are formed during the fibril formation process may in fact be more toxic, though again it really depends on who you ask.

How the toxicity is manifest is also totally unclear - is this a loss of function (proteins which aggregate disappear, so they can no longer do their job), gain of function (proteins which aggregate now interact with other things, leading to some new and bad outcomes) or somewhere in between? How does the cellular quality control system interface with all this? Why are certain cell types much more susceptible than others? How does the disease spread in the brain?

There are a lot of very smart people doing some amazing work. If you're interested, off the top of my head I'd take a look at work by Sue Lindquist, Simon Alberti, Marc Diamond, Don Cleveland, Virginia Lee, Eric Ross, Paul Taylor, Rick Morimoto and David Eisenberg (just to get you started!).

The one thing I would say is that I wouldn't treat this as cause for concern for interpersonal spread. If there was a real risk of contamination from (say) surgical instrumentation (as there was with vCJD in the UK) there would be extensive evidence for this (just in terms of a numbers game). Which isn't to say if you put someone's brain in your brain you won't develop the disease, but at that point you probably have bigger issues to worry about...

In my opinion, a much more exciting story relating to ALS was published in Cell a couple of days ago;

Patel, A., Lee, H. O., Jawerth, L., Maharana, S., Jahnel, M., Hein, M. Y., … Alberti, S. (2015). A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell, 162(5), 1066–1077.

[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942086/

[2] http://www.ncbi.nlm.nih.gov/pubmed/24857020

[3] http://jem.rupress.org/content/209/5/889.full

[4] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820001/

I thought that said "porn" on first reading. So it doesn't exactly make you go blind...

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