Informing the Next Generation of Parkinson’s Therapies
How can we improve the next generation of therapies for Parkinson’s disease (PD)? Alexandra Nelson, M.D., Ph.D., of the University of California, San Francisco, was recently awarded a Stanley Fahn Junior Faculty Award from the Parkinson’s Disease Foundation (PDF), a division of the Parkinson’s Foundation, to find out. Using a groundbreaking technology called optogenetics and the $300,000 multi-year award from PDF, Dr. Nelson is advancing what we know about the brain’s cells and circuits and how they are affected by the gold standard PD drug, levodopa. Here, she shares her early findings.
Q. Can you summarize your PDF-funded research?
A: Our goal is to understand how levodopa changes brain activity, so we can improve current therapies and find better ones. Early in my training, I was amazed to see the benefits of levodopa in people with early stage PD. However, in the later stages of PD, levodopa both alleviates symptoms and triggers dyskinesia (uncontrolled twisting movements). Why would the same drug produce positive and negative effects? My team is using a technique called optogenetics and a mouse model of Parkinson’s to find out. We’re observing up-close how levodopa affects cells and circuits in the mouse brain.
Q. What is optogenetics?
A: Optogenetics is a groundbreaking technology that uses light to turn specific brain cells “on” or “off” and observe the effects. The technique is helping us to understand how different types of brain cells work. For example, in the striatum — a key movement region of the brain affected by PD — there are two main types of cells. We think that they control the body’s movement in different ways, but older techniques didn’t allow us to differentiate what each cell type was doing. For example, is one helping in PD, and the other causing problems? Optogenetics enables us to monitor both cell types in mice before and after levodopa treatment and compare the responses. The findings will help us to understand the cell types, and whether they are involved in the drug’s benefits or side effects.
Q. Can you share early findings? How might the results impact the community?
A: Yes, our experiments are already yielding exciting results! Researchers have long suspected that Parkinson’s leads to an imbalance in activity between the two cell types in the striatum and have thought that levodopa may work by re-balancing them. However, this has never been proven in living animals and has remained controversial. Now, our research has proven both ideas — confirming that an imbalance exists between the two cell types and that levodopa can restore the balance. But our studies also showed that during dyskinesia, levodopa may instead unbalance cell activity in a specific population of cells. Further research is needed to understand this observation. But it’s possible that targeting this population of cells, and preventing the imbalance, might lead to better therapies. Overall, our hope is that this knowledge will lead to targeted treatments for Parkinson’s that can alleviate symptoms without triggering dyskinesia.
Q. Is there anything else you’d like to share?
A: I am inspired by the people with Parkinson’s disease and families with whom I work, especially their grace and ability to cope with this disease. I take this inspiration back to the lab, which gives my students and me the urgency and motivation to continue our work. I would add that PDF support, which is a risk given I am an early-career investigator, has been absolutely critical to kickstarting our ideas.