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Real Progress in Parkinson’s

There have been some potentially significant developments in Parkinson’s disease, which is a good thing to be able to report. As populations age around the world, PD has been on its way up, but therapies for it have not been, despite a good deal of work in the field. But it looks like some clues are starting to come together.

The misfolded protein that piles up in the substantia nigra of Parkinson’s patients is alpha-synuclein. For many years, understandably, that led to a focus on that protein in that tissue, but there’s more to the story. Misfolded alpha-synuclein is found in other brain regions, for one thing, and it’s found in other tissues besides the brain. And those realizations have led to an interesting hunt over the years. The spread in the brain seems to be coming up from the brainstem, the vagal nerve in particular. That one’s hooked up to a lot of important stuff, including the GI tract. And most interestingly, gastrointestinal symptoms are correlated with later PD onset (chronic constipation, among others), and cellular synuclein accumulation (Lewy pathology) has been shown to occur in GI tissue up to twenty years before diagnosis via the overt Parkinson’s symptoms. Since these realizations, the misfolded protein has been shown to apparently spread via a prion-like mechanism, coming up from the gut towards the brain.

But where in the gut does misfolded alpha-synuclein originate, and why does it form? The working theory is that it’s formed after repeated immune response in the GI tissue. This is a complicated question – anything to do with the immune system is a complicated question – and there’s room to argue about whether some of the GI changes are causes or consequences of Parkinson’s pathology. But the evidence continues to accumulate. The appendix is known to be important in gut immunity, and misfolded synuclein has been found in it.

Now there’s a paper out (from a large multinational team) that shows that surgical removal of the appendix is correlated with lower risk of Parkinson’s. This looks like a strong result, coming as it does from two independent databases with the health records of nearly 1.7 million patients (!) Compared to the general population, the risk of developing Parkinson’s goes down by 19% in patients who have had appendectomies (and note that these are generally decades before any diagnosis of Parkinson’s gets made). This sort of study had been tried before, with mixed results, but this is by far the largest and the one with the longest follow-up data available. These authors also confirm the presence of misfolded and misprocessed alpha-synuclein protein in appendix tissue, and they furthermore show that lysates of such tissue quickly cause solutions of regular alpha-synuclein to aggregate. These misfolded proteins are found in people all the way from infancy, interestingly.

So it’s looking more and more as if the trail of Parkinson’s does lead back to the GI tract, and perhaps from there back to the appendix. But what is it about aggregated synuclein that starts killing off neurons? There’s another new paper that sheds some light on that, from a multinational group led out of Australia. Inflammation has long been suspected as the culprit with synuclein fibrils, and this paper shows that inhibiting the NLRP3 inflammasome has significant consequences. In multiple mouse models of PD pathology, administration of an inhibitor compound (MCC950, also recently shown to be active in models of colitis) seems to protect against synuclein-driven cellular effects. Combining that with the presence of NLRP3 activation markers in post-mortem human Parkinsonian brain samples, and you have a compelling case. It’s one that makes a lot of sense – this system has already been a target in neuroinflammation research, and it’s known to respond to stimuli such as crystals forming in the cytosol (cholesterol, uric acid, etc.) or to the presence of small particles that have been imported into the cell.

The picture that emerges is of an important cellular protein, alpha-synuclein itself, that has (unfortunately) an alternate folding state that’s too easily accessible. Repeated immune system activation in the gut produces this form, and this misfolded beta-sheet-rich form propagates via a prion-like model. Since it’s particularly abundant in the nerve terminals, it has a chance to slowly work its way up the vagal nerve system into the brain, and along the way, it’s setting off continuous inflammation via the NLRP3 response which (along with the physical problems brought on by the aggregated protein itself) ultimately prove fatal to many cells.

The exact mechanisms of that last part aren’t quite worked out – there could be further accelerated seeding of pathological aggregates, impaired protein clearance, or some other cytotoxic mechanism brought on by the inflammatory pathways, or some of each of these and more. But the finding that interrupting the inflammasome activity seems to interrupt synuclein pathology is a really significant clue, and a stroke of good luck mechanistically. NLRP3 inhibitors of this type would seem to be solid med-chem leads for a Parkinson’s drug discovery program, and I would assume that this is underway (or will be as soon as people read this paper!) Good news all around.

 

33 comments on “Real Progress in Parkinson’s”

  1. Hap says:

    Would this imply that appendectomies for people with a high likelihood for developing Parkinson’s would be a good idea?

    1. JSR says:

      No, because apparently LRRK2 mutants don’t show the benefit from appendectomy, nor do people who get the surgery later in life.
      (disclaimer: I didn’t read the paper, but saw these points called out explicitly in another blog on it. Maybe it would have been faster to just read the paper than read all these partial summaries of the paper!)

    2. Richard Bernstein says:

      Before we get too excited: it could be an epiphenomenon. For example, misfolded Alpha Synuclein leads to poor gut motility and that causes appendicitis, which leads to appendectomy. All retrospective studies are contaminated by that possibility, which is why treatments can’t be based on them. However, retrospective studies lead to hypotheses that can be tested in trials. Perhaps not doing appendectomies in people without appendicitis because they are “at risk” for PD–thats a bit extreme.

      1. David Young says:

        I don’t quite get it…. wouldn’t that make PD more common in patients who had appendectomies?

        1. Pete says:

          Yes, RB’s mechanism does the opposite of what he claims.
          It could still be two correlates to an underlying causation: perhaps whatever causes PD also makes appendicitis less likely.

          That does sound rather more weird and unlikely, though, given we know PD and (other) GI problems are positively correlated it’s not clear why PD and appendicitis should be negatively correlated.

  2. MrXYZ says:

    A Science paper from 2017 (http://science.sciencemag.org/content/357/6354/891?iss=6354) showed a striking epidemiological correlation between beta-adrenergic receptor agonists and antagonists and PD risk (agonists decreasing risk and antagonists increasing risk). While the paper postulates changes in histone modification and alpha-synuclein production as the mechanism, I wonder if modulation of gut function/inflammation via adrenergic receptors might be a better explanation.

    1. Chris says:

      I’m not sure if all parts of this study will withstand replication:

      https://www.ncbi.nlm.nih.gov/pubmed/30039155

      I understand that more of the factors in the epidemiological analysis need to be considered, try this report for a view

      https://scienceofparkinsons.com/tag/salbutamol/

  3. Some idiot says:

    Hmmm…. Very interesting… Given that there have been reports that GLP-1 drugs have an impact on Parkinson’s, it is tempting to speculate that it may have some mechanism starting in the gut… As well as (or instead of) an effect directly in the brain? Anyone in the area (I’m not) have any comment?

  4. anon the II says:

    Two comments.

    Every time I see NLRP3, I think of NRPS or New Riders of the Purple Sage. Does this happen to anybody else?

    Also, where does that iso-Demerol degradation product, that seemed to generate a great Parkinson’s model in drug addicts, fit into all this?

  5. Marcus Theory says:

    So do people with Crohn’s or colitis develop Parkinson’s at a higher rate?

    1. navarro says:

      i don’t know about that but people with crohn’s do show an increase in the lrrk2 mutation.

    2. David says:

      It would appear so:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888265/ shows ” a strong genetically defined level of comorbidity between PD and Crohn’s disease.”

  6. luysii says:

    Another way to treat/prevent parkinsonism would be breaking up alpha-synuclein aggregates after/before they occur. A small molecule has been found which does just that in animal models (along with clinical improvement).. It is the horribly named SynuClean-D. Here is the structure described verbally. Start with pyridine. In the 2 position put meta nitro benzene, in the 3 position NO2, in the 4 position CF3, 5 position CN (is this trouble?) and 6 position OH. Do the CN and NO2 groups make your teeth itch?

    For details see — https://luysii.wordpress.com/2018/10/17/has-the-holy-grail-for-parkinsons-disease-been-found/

    1. Some idiot says:

      Yes… also (as a process chemist) makes me curious to know how thermally stable it is… Plus the 5-CN plus 6-OH makes me think Michael acceptor…

      1. milkshake says:

        it is not a Michael acceptor but electron deficient biaryl that will pi-stack nicely with tyrosine residues in protein. The cyano group may act as a reversible SH group acceptor. Of course there is possibility for metabolic activation to electrophilic species such as N-arylhydroxylamines, which are part of the tox liability of nitroaryl compounds. it is an ugly looking compounds but patients have been taking even more ugly stuff, especially from the old antiparasitics (that work by unknown mechanism) and nitrofurane/nitrimidazole antibiotics.
        I would check for mitochondrial toxicity (there are known uncoupling agent pesticides from the DNOC class)

        1. Some idiot says:

          I am thinking addition and then elimination of water to form an irreversible addition… But yes, it is not the world’s most pretty structure. But, as you say, uglier drugs are being taken today. Question is of course whether or not the positive effects outweigh any eventual side effects… as usual…

          1. luysii says:

            It’s great to see the readership apply organic chemical reasoning to figure out how the compound may work (and a lot of fun to do). We know a lot about organic chemistry.

            However this also points up how precious little we know about the system we are investigating. How did they find SynuClean-D?? Like this. ” Recently, we have developed an accurate and robust high-throughput screening methodology to identify α-Syn aggregation inhibitors “.

            Hardly from first principles. Drug chemists need fundamental research to point them towards targets (which is why Derek has taken more and more to writing about fundamental biology, physiology etc. etc.)

  7. BiotechFanatic says:

    Very cool. The first “Inflammasome” link links to a wikipedia page

  8. An Old Chemist says:

    Today’s Biospace has summarized this paper about the connection between Parkinson’s and appendix removal. It is easy to follow for non-biologists:

    https://www.biospace.com/article/people-who-had-their-appendix-removed-at-lower-risk-of-parkinson-s/?keywords=parkinson

  9. HTSguy says:

    There is evidence that the formation of prion-like aggregates is a regulatory mechanism for some proteins (10.1101/cshperspect.a021774). Perhaps alpha-synuclein uses such a mechanism but has nasty side-effects and yet isn’t selected against because they primarily occur past the age of reproduction and child-rearing.

  10. loupgarous says:

    Here’s the takeaway from the Science paper:

    “In addition, we found that the age at first hospital diagnosis of PD was delayed (by 1.6 years) in people with PD who had undergone appendectomy at least 20 years prior. Upon further analysis, an appendectomy was protective against PD for individuals living in rural areas but not for those in urban communities. In rural areas, PD is linked to environmental factors, particularly to the use of pesticides (36, 37, 47). Hence, our findings suggest that the involvement of the appendix in the development of PD may be modified by environmental risk factors. Together, the evidence from our large population-based study shows that the appendix affects both the absolute risk of PD and age at PD diagnosis. The effect was most pronounced when appendectomy was performed early in people living in rural areas, which implies that the appendix could function in the mechanisms triggering PD pathology and that the actual trigger could be environmental in origin.”

    The main protective effect seems to be in rural populations, not urban ones. Something in Swedish farms is creating a problem appendectomy solves.

    1. Shazbot says:

      ..Maybe? It also could be things found in Swedish farms over fifty years ago. Or forests, for that matter. I’d be careful to jump to any specific conclusions from just this, it could be any number of things.

      1. loupgarous says:

        The converse might be true, too – clean living in the Swedish countryside might have kept α-synuclein levels down to a point where appendectomy exerts a protective effect counter-balanced by toxins found only in Swedish cities (as Shazbot correctly points out, fifty years ago). It might be a toxin that accumulates to a greater extent in Swedish cities.

    2. Nick K says:

      I seem to recall that exposure to organophosphate pesticides is correlated with PD. Has anyone got an update on this?
      Some anecdotal evidence: my late uncle developed PD very early in life (mid thirties). He was a sheep farmer in North Yorkshire who dipped his animals with organophophates in Spring and Autumn every year.

      1. Anonymous says:

        Organophosphates : PD. I also recall something like that, but it appears to be more complicated. The free summary of this: “Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease.” Neurology, 2014, 82(5) 419-426; DOI: 10.1212/WNL.0000000000000083 says:

        “Results: All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides.” No further access, so I can’t see which ones (any organophosphates?) did not correlate with PD.

        But I also recall stories (no data) that urban (insect, rodent) exterminators had a higher incidence of PD or other neurodegenerative diseases. (I’m looking for the video of the “treatment” of cockroaches with periplanone B but I can’t find it. It’s primarily a male sex excitant and the critters burn themselves out but die happy. Periplanone B is not used commercially as far as I know.)

    3. Lane Simonian says:

      Maybe this explains the link between pesticides, appendectomies, and Parkinson’s disease risk.

      “Increasing evidence suggests that environmental neurotoxicants or misfolded α-synuclein generated by such neurotoxicants are transported from the gastrointestinal tract to the central nervous system via the vagus nerve, triggering degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and causing Parkinson’s disease (PD).”

      Appendectomy History is not Related to Parkinson’s Disease.

      CONCLUSIONS:
      The results of the study suggest no effect of appendectomy on the emergence and clinical manifestations of PD. The removal of the appendix is possibly not sufficient to suppress the exposure of the brain stem to α-syn via vagal retrograde transport. Further studies are needed to elucidate the role of appendix in PD.

      https://www.ncbi.nlm.nih.gov/pubmed/28387683

      So an appendectomy maybe not be generally protective, but protective when one has been exposed to pesticides over many years. If true, this is a sliver of good news for me since I fit into both categories.

      I will add the following without making any comments.

      https://www.ncbi.nlm.nih.gov/pubmed/28640632

  11. Blunts says:

    The mptp compound is a mitochondrial uncoupler or something like that. It’s selectively taken up to dopaminergic cells by DAT. Probably not a similar mechanism of action?????

  12. JohnH says:

    Does “Studies have found an association between smoking tobacco and a reduced risk of Parkinson’s disease” provide another clue as far as the gut, Appendix or Vagal nerve go?

  13. me says:

    Appendectomy as prophylaxis? Or a course of anti-alpha synuclein mAb early in life to misfolded protein in the peripheral system?

  14. JBstein says:

    I don’t buy it. the statistics are too weak to hold over such a broad range. don’t like the migrating proteins neither. the body might simply have the same response to inflammation in two different locations. I would go down these lines rather https://www.statnews.com/2018/10/29/alzheimers-research-outsider-bucked-prevailing-theory/

  15. G says:

    mesencephalic astrocyte-derived neurotrophic factor. the unfolded protein response is a point of attack for many diseases throughout the body.

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