[Rhonda]: I kind of wanted to ask you a little bit about before we get into that, just, you know, how many people, I mean, worldwide, in the U.S. have Parkinson's disease and maybe some of the environmental versus genetic causes of Parkinson's disease or what we know, what the field knows about that.

[Giselle]: Right. So, I mean, I think in general, so the idea is that 1 in 100 over the age of 50 have Parkinson's disease and don't know the exact number.

[Rhonda]: So it’s the second leading neurodegenerative disease behind Alzheimer's?

[Giselle]: Second leading. Yeah. Definitely the second leading. Right. Behind Alzheimer's. And I think in terms of genetics... So, in general, we think that genetics play an, you know, certainly there are genetic risk factors, but in terms of strong genetic contributions, most of that data seems to be in young-onset. By young onset, I mean, younger than 35, for example. Not as common over the age of 35, although now certainly we're recognizing that there are these risk factors like LRRK2, for example, where there may be running in certain ethnic groups where there may be some higher predisposition.

[Rhonda]: LRRK2 is a gene.

[Giselle]: Right. LRRK2 is a genetic mutation. But still, in general, I think the idea is that most of these genetic predispositions are happening in younger-onset people and that in the older, and again, older being anybody over the age of 35, as an example, or over the age of 40, at least, that there's probably a mix between as, you know, environmental and genetic factors. And we've heard that again by some work by a number of very important investigators who've been able to show us, you know, some of that epidemiological data, which is the idea that there's been some higher risk in rural settings than in urban settings, the idea that environment does seem to play a role. And so, in general, we would say, still in Parkinson's disease, that it is sort of there's a number of different risk factors. Some may be genetic as we get older, those genetic influencers may have some specific role in certain populations in general, but that we would say that it's environmental risk factors and maybe even things that play a role in genetics that are related to metabolism, how we metabolize, for example, herbicides. And also the other genetic aspect of it is still questions related to, you know, plasticity itself, repair mechanisms, is another example.

So you can see that it gets complex pretty fast in terms of what genetic risk factors may be and what environmental factors may be. And I guess the point is people are beginning to recognize that Parkinson's may be kind of a common final pathway of a number of different mechanisms, which kind of makes it challenging in a way because trying to isolate every single one of those targets can be hard because there may not be one single risk factor, for example.

[Rhonda]: Right. Exactly. Yeah. I was talking to you a bit before we started rolling that basically the field seemed to really advance back in the 1980s when, you know, this precursor to a neurotoxin, MPTP was, you know, like found to basically cause parkinsonian symptoms in people, I guess, chemists that were synthesizing it, or even I think IV drug use.

[Giselle]: Yeah. The IV drug users. Chemists seemed to not get the problem, but the IV drug users, right? Exactly.

[Rhonda]: And basically this, you know, this neurotoxin essentially inhibits mitochondrial function and it crosses the blood-brain barrier. It can, you know, affect all sorts of, you know, brain regions and dopamine neurons. But the thing that was very disturbing was the similarities between some of these insecticides and herbicides, like rotenone and paraquat that essentially have the same mechanism of action, also can cross the blood-brain barrier and are used in animal models...

[Giselle]: Exactly. They're very effective, aren't they? Yeah. I think the thing about it that, you know, obviously that the finding of the MPTP in the 1980s, so to clarify essentially what happened was in the 1980s, there was a sort of an outbreak, if you will, of Parkinson's and what was so unusual about it is that these particular individuals, and there were about eight individuals that say that presented around the Bay area in various emergency rooms had essentially developed parkinsonian features overnight, and nothing like that had ever been seen. And there was sort of some really interesting investigative work that had been done to try to identify what was the commonality between all of these individuals and what they found right off the bat was they had been heroin users and that they had gotten some access to some, you know, synthesized heroin, essentially that had been tainted with this protoxin, if you will. So MPTP is sort of a protoxin. It gets delivered to the brain and there it gets converted to MPP+.

But in essence, they were not aware, of course, that this was in the kind of the heroin itself. And it had been synthesized inadvertently by these chemists because they had changed the kind of the protocol, if you will, in how they were synthesizing this compound by changing the temperature. Simply changing the temperature of the reaction had brought out this particular toxin. And when they injected it directly into their vein, they essentially blew out their nigra, so killed dopamine cells. And we know that for a fact because for some of these individuals who passed on, the brains were looked at, and also they had gained access to some of the same material and used it in primates and were able to see replicate, Parkinson's essentially be able to see that they had killed cells that caused dopamine depletion, that it disturbed circuitry, and that it caused motor impairment like Parkinson's disease.

So the difference was this was acute, right? But I think what was so important about that was that, one, it created a model that we could study, two, it validated the whole idea that there are environmental products or environmental exposures of toxins that could absolutely contribute, right, to a neurodegenerative disorder. And so, that kind of reconfirmed this epidemiological data that rural aspects of where you live may influence, you know, or contribute at least to this kind of disease of aging, may be accelerating it, or certainly in this situation, bringing it out even faster. So, you know, again, affecting how fast people may get it.

[Rhonda]: Right. You mentioned earlier how there's a, you know, probably a lot of combining factors, perhaps additive, in some cases, you know, so you may have higher exposure to some of these pesticides, if maybe you're a farmer. In fact, farmers have been shown to have a higher incidence of Parkinson's disease if they're working with paraquat. So, you know, in combination with other things, maybe being sedentary and having a lot of inflammation, and just like the, you know, the perfect storm of environmental factors that can, you know, increase your risk.

[Giselle]: Right. Exactly. And I think that's the point. It's hard to, you know, necessarily always pick out one thing. And what happened to that MP..., you know, obviously would tragically happen to these individuals, fortunately, we've never seen an outbreak like that since then, you know? But it does sort of point out the idea that, you know, right, that there may be a contribution of things either over time or a number of different risk factors that can certainly contribute to this. Right.

[Rhonda]: I think with those two, in particular, those two, you know, rotenone is an insecticide and paraquat is herbicide. And I know that rotenone I think is really only used now in the U.S. to kill fish, like a piscicide or something. I don't know how much of it's in the water. I mean, it's kind of like, you know, all these things to think about. But paraquat, I think it's like pretty much phased out. It's restricted use in the U.S. maybe in developing countries and stuff. But, you know, the question becomes, "If I have a, you know, my produce is not organic, but I'm exercising and I'm, you know, I'm avoiding refined sugar and I'm doing everything else. Maybe it's not such a big deal. I don't know. Maybe I have a genetic risk factor, maybe I don't." There's a lot of things to consider. Maybe you don't want to have a complete fear. I've decided I'm eating organic just because I do eat a large quantity of them and some, you know, but blending them in smoothies and stuff. But, you know, it is one thing to consider of many different, you know, possible risk factors.