Many advances in neurobiology of disease have stemmed from Dr. Ted Dawson’s identification of the mechanisms of neuronal cell death and the elucidation of the molecular mechanisms of neurodegeneration. He pioneered the role of nitric oxide in neuronal injury in stroke and excitotoxicity and elucidated the molecular mechanisms by which nitric oxide and poly (ADP-ribose) polymerase kills neurons and discovered Parthanatos. His studies of nitric oxide led to major insights into the neurotransmitter functions of this gaseous messenger molecule. He co-discovered the neurotrophic properties of non-immunosuppressant immunophilin ligands. Dr. Dawson has been at the forefront of research into the biology and pathobiology of mutant proteins linked to familial Parkinson’s disease. These studies are providing novel opportunities for therapies aimed at preventing the degenerative process of PD and other neurodegenerative disorders.
The following has been paraphrased from an interview with Prof. Ted Dawson on March 26th, 2018.
(Click here for the full audio version)
In people with Parkinson’s Disease, do we have any idea what the ratio is between dead neurons and those that are still alive but have just lost function? (among dopamine cells in the substantia nigra)
It’s very clear in both animal models and humans with PD that there is loss of neurons. When patients at advanced stages of PD die and their brains are analyzed, 80-90% of dopamine neurons are gone. But in patients living with PD it is not clear how many neurons they have lost vs. how many just aren’t functioning as dopamine neurons. We are taught as students that to manifest Parkinson’s disease you need to lose 80% of your neurons, but that is only from information at the very end of the disease process. It depends on what stage of the disease the person is at, but the ratio is probably closer to around 40% that have died and 40% that are just not functioning.
If we were able to clear the alpha-synuclein tangles in the brains of people with PD, would we see a regain of function of those dopamine producing neurons?
That would be the hope. Our animal models are designed to hit mouse dopamine neurons really hard because drug companies and granting agencies want answers relatively quickly, grants generally last 3-5 years so we are forced to use models that last for that amount of time. We can’t do the really long studies that would be needed to more accurately model the disease. However, the hope would be that if we can clear the protein build-ups we would start to see a regain of function.
Could you briefly describe the link between deficiencies in mitochondrial complex 1 (MC1) and Parkinson’s disease?
There is evidence that has accumulated that there are detriments to MC1 in people who have PD. What lead us to believe that was the discovery of MPTP, which is a powerful toxin that causes PD in models and in humans. Most of the work shows that it works by inhibiting MC1, though there are a couple of labs that show it may be killing dopamine neurons by other mechanisms. It was also found that there are problems in platelets of patients that had MC1 deficiencies, as well as some post-mortem data that showed a similar link.
Where the field is now is in determining what comes first. Does MC1 deficiency drive the disease or is it a response to other things going on? Our lab is trying to understand how cells die in response to mitochondrial dysfunction, that has lead us to develop potential targets to treat this problem. This would be very promising because the data out there shows that the majority of people with PD have problems in MC1, but again, we still don’t know if it is a cause or a response.
Is the same true of something else your lab studies closely, elevated levels of Nitric Oxide (NO)?
There is clear evidence that there are elevated levels of NO stress in people with PD and in animal models. But it also gets back to this chicken and egg problem. NO is probably a response to what alpha-synuclein is doing to the cell that then leads to other problems in a feed-forward mechanism.
Another focus of your lab is on a protein called PARIS, have you moved towards developing any inhibitors of this pathway?
We are really excited about PARIS. We have shown that if you knock out PARIS it is protective in various animal models. We have identified some inhibitors of PARIS, but stay tuned, we are trying to get them published. If we get them published hopefully it will create a lot of interest.
Which of the various methods being tried to target GBA pathways do you think might be most beneficial?
I don’t know what trial to bet on. This is why clinical research is so important, the answer to that question is entirely dependent on doing the clinical trial and seeing which one works. The pre-clinical data doesn’t strongly suggest one over the other. It is clear to me that in people who have GBA mutations, for reasons that aren’t fully understood, synuclein aggregates more effectively. If I was a GBA patient I would be looking for ways to make synuclein less toxic and wait to see on ways to manipulate the GBA system.
Everywhere we look in PD research we have puzzle pieces that give clues as to how to treat this disease. Do you believe we have enough puzzle pieces uncovered to get to the disease modifying therapies we are all looking for?
My quick answer to that is that I think we are at a point where we have enough strong data that it is worth the investment from biotech and pharma to test certain hypotheses and to do the clinical trials. The most promising puzzle pieces are: Parkin activators, LRRK2 inhibitors, alpha-synuclein antibodies and vaccines, c-Abl inhibitors, PARIS inhibitors, and things that manipulate the GBA system. I think one of those is going to be shown to work in people with PD, the question is how much are they going to work? Are they going to result in a 20% slowing of the disease or are they really going to make a huge impact? No one knows the answer to that, that is why it is so important to continue to work out mechanisms and dig deep. If you look at the history of medicine, it is very rare that you have a homerun right at the start, it is usually small effects that build over time to a large effect. Let’s do the trials, but let’s also invest in the basic science so we can uncover more targets for future trials.
Click here to learn more about the work of Prof. Ted Dawson
First two questions are questions I’ve been afraid to ask…. Kudos for asking the questions you my not want the answer to first.
Was encouraged by Prof Dawson’s replies.
That’s a posting full of inihsgt!
It was a nice read. A very insightful interview. Those are some really helpful studies on neurobiology.