From Skin Cells to Brain Cells: How PDF Fellows Are Using Genetics to Move the Field Forward

For the past three years, the Parkinson’s Disease Foundation has been funding the research of young scientists in the New York metro area through our Lucien Côté Clinical Genetics Initiative.

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Dr. Beck (VP, Scientific Affairs, PDF), Dr. Pan and mentor Dr. Yue; Dr. Li and mentor Dr. Noggle; and me.

It’s exciting because in studying how genes are affected by Parkinson’s, we can learn more about what goes wrong with PD overall … even in cases without a genetic cause.

Last Wednesday, we had a visit with two awardees and their faculty mentors at PDF’s office to get an update about their research. Both awardees are using an experimental technique called “induced-pluripotent stem cells” where they can actually take skin cells from a person who lives with PD (caused by a certain genetic mutation) and transform them into brain cells!

Specifically, they make the skin cells into dopamine neurons, which are the brain cells especially affected in PD. This provides an amazing tool for them to study Parkinson’s — they can study how the dopamine neurons (which are sick and have PD) behave, and how different genetic mutations affect them. This gives great insight into what might cause PD.

cote_aiqun li_awardees2Aiqun Li, Ph.D., staff scientist at the New York Stem Cell Foundation, is studying a mutation in a gene called glucocerebrosidase, or GBA, which makes an enzyme that is important in breaking down toxic substances and recycling worn out parts of cells. Dr. Li took skin cells from two identical twins, both who have a mutation in GBA, but only one of whom developed PD. He is studying dopamine neurons made from each twin’s skin cells to study any differences between them, in the hopes of finding out why one twin has PD and the other does not. So far, he has found that both twins have elevated levels of alpha-synuclein, a protein that tends to get clumped in people who have PD, and decreased amounts of dopamine. However, the twin with PD showed even lower levels of dopamine, as well as higher levels of an enzyme called MAO-B, which breaks down dopamine. When he treated cells with both GBA and chemicals that stop the function of MAO-B, he found that alpha-synuclein levels decreased to normal, and dopamine levels increased. This suggests that for people with this specific mutation, a combination therapy of both the GBA enzyme and MAO-B inhibitors (which are already being used to treat PD) may be helpful. More work needs to be done to confirm this.

cote_ping-yuepan_awardees8Ping-Yue Pan, Ph.D., a postdoctoral fellow at the Mount Sinai School of Medicine, is studying a mutation in a gene called synaptojanin 1 that is associated with PD. Synaptojanin 1 makes a protein that helps to recycle the vesicles, or containers that hold chemicals called neurotransmitters. These vesicles help neurons communicate with each other, by delivering neurotransmitters such as dopamine from neuron to neuron. Dr. Pan found that dopamine neurons with this mutation have much less complex structure, especially in the dendrites, which are branches that receive neurotransmitters from other neurons. She also found this mutation results in dopamine being broken down much faster than is normal, which means there is less dopamine available. This mutation in synaptojanin 1 is relatively new, and was only found by scientists a few years ago. Dr. Pan’s work in finding out out how this mutation specifically affects dopamine neurons will help us learn more about the underlying causes of PD.

Dr. Li and Dr. Pan have plans to collaborate in the future, working on induced-pluripotent stem cells that carry a different PD mutation. Their respective mentors, Scott Noggle, Ph.D., and Zhenyu Yue, Ph.D., also joined the scientific discussion at the meeting and are looking forward to having their two laboratories work together.

PDF is thrilled to provide early career support to these creative, young investigators working together to help solve Parkinson’s disease.

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