Real Progress in Parkinson’s

By Derek Lowe

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.

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