2015 NETPR Investigator Vignette

Title: PGC-1α Therapy for Parkinson Neurodegeneration

Investigator: Howard J. Federoff, MD, PhD; University of California, Irvine

Parkinson's disease comes in two flavors-very rarely there is a strong genetic basis, which means that if you have inherited a gene or you've lost the function of two genes from either parent, you'll get the disease with nearly 100-percent or 100-percent certainty. Those are rare. The predominant form of Parkinson's we call sporadic Parkinson's, which accounts for more than 93 or -4 percent of all Parkinson's disease.

So, if one understands that there must be a minor genetic component, then what else is involved? Well, we call that an environmental contribution. We are exposed to air, water, food, but we may also have occupational-related exposures.

And so we think that this work at trying to identify what are those environmental exposures, how do they link to inherited risk based on Mom and Dad-what they've conveyed-can we understand how those synergize?

So, the general idea of systems biology or systems medicine, when we talk about it in the context of clinical care, is that you can make multiple measures and correlate those measures using a framework to understand what's going on in a more holistic way.

A single one might have told you a little bit about what was going on with that patient, when you integrate them, they actually produce what we call a network because they're interacting with one another. And when the network is understood, it actually tells you something about this integration across the whole person. So the concept that there is an at-risk individual-and it could be because they had antecedent head injury-and now there is this disrupted network. They formerly were well, but now they have a disruption. And it may not yet be evident that that disruption will definitely lead, in some period of time, to Parkinson's, but it might. And if one understood that network and could measure it quantitatively, and you knew what interventions that you could [use to] mitigate the risk of that at-risk individual progressing to disease, that's a home run. That's a way that you really deploy the systems approach to categorize individuals, and when you understand what drives their emergence of disease, you can intervene early. And you will have a chance to actually blunt that progression to the manifestations that wind up becoming life-limiting.

So, this generalized model of environments summating with inherited vulnerability is going to explain a lot of neurologic disease. And I will go even further: Almost every major category of human disease is going to be explained by that interaction, and clinically we are just not smart enough to know how to measure it. But we are going to get there.

The DoD program-the NETPR program-has had a profound impact: One, at the early stages, thinking about, "Well, how do you do grant funding to have a big impact with small dollars?" And secondly, "How, as an investigator, do you develop a network of collaborators you can rely on to do the kind of work that can sometimes be field-shifting?" And I think we're just at that point right now.

So, one of the areas of work that we've done is focused on trying to understand how to dial up the amount of the master regulator for energy production, which is called PGC1alpha, and the way we're doing this is using a repositioned or repurposed drug which has this new mechanism that we've discovered, which directly turns up in a dose-dependent fashion-the expression of PGC1alpha. And then downstream of that, you make more energy, you protect cells, you cause inflammation to go away. And at the same time, you produce what's called an antioxidant effect, so the discovery of PGC1alpha that was actually consequent to some early funding that came to several investigators-ourselves included-who all decided to collaborate. So, we published a very, very high-impact paper about five years ago that probably no one would have thought possible had that funding not been available. And then the lead investigator sensed that there was this moment where you can get everyone in the world working together on the same problem to want to collaborate-and what was revealed was the PGC1alpha. I mean it just fell out, and no one else would have found that.

I've never seen a better focused, more concerted effort to find the most talented investigators doing the most innovative and high-impact work than the NETPR program has sought and funded. And I think it's a model, and I think it's one that, if as a nation, we really wanted to be competitive with those other nations that are now supporting research as if it's tied to their gross domestic products, this is the model that I would adopt.