My PD Story

Exploring DNA “Safety Caps” as a Potential Source of Neuron Loss in Parkinson’s 

The biological hallmark of Parkinson’s disease (PD) is a progressive loss of neurons in the brain, particularly ones that produce the neurotransmitter dopamine. What makes these neurons uniquely vulnerable to malfunction has been a major subject of research, as understanding their weaknesses could lead to new treatments that protect them from failing.  

Oxidative damage (where chemically reactive forms of oxygen molecules cause disruptions in cells) has been linked to PD-associated dopamine neuron loss. However, we still don’t know exactly how reactive oxygen molecules lead to the death of neurons.  

Edward Burton, MD, PhD, and recipient of a Parkinson’s Foundation Impact Award, believes the answer may lie with telomeres, the protective “caps” on chromosomes linked to aging. This is one of the most detailed studies to date on the role of telomere damage in PD. 

What is a telomere?

Telomeres are the long stretches of repeating DNA patterns found at the ends of chromosomes. They act as a "safety cap," protecting chromosome ends from deteriorating or being inappropriately recognized as areas of DNA damage. This is one of the first studies to link telomeres to Parkinson's disease.

Cells need a way to keep the delicate ends of their DNA protected from deteriorating or being incorrectly recognized as areas of DNA damage. The solution to that problem is telomeres, the long stretches of repeating DNA patterns found at the ends of chromosomes. These patterns protect chromosome ends, but get progressively shorter every time a cell divides, limiting the lifespan of cells that routinely divide, such as skin, blood and intestinal cells, and contributing to aging. 

The importance of telomeres in neurons has not been well investigated, mainly because neurons do not divide once established and therefore their health and lifespan should not be limited by telomere shortening.  

Dr. Burton and collaborators from their labs at the University of Pittsburgh in Pennsylvania, have recently discovered that another mechanism may link faulty telomeres to PD. While neurons may not show telomere shortening as a result of cell division, damage to their telomeres — particularly oxidative damage already linked to PD — could still trigger emergency DNA damage responses that impair neuronal function and eventually cause cell death. 

“This is an exciting new research area in response to several recent discoveries about telomere biology and its role in the aging brain” - Dr. Burton 

To test his hypothesis, Dr. Burton will first take postmortem brain tissue samples from people who had PD and investigate if their dopamine neurons had signs of oxidatively-damaged telomeres. This will tell him if he’s on the right track with his theory that damaged telomeres are associated with PD.  

For the next part of his research, Dr. Burton will use genetically modified zebrafish, in which he can trigger oxidative damage in neurons on demand using a technique called chemoptogenetics. By specifically causing oxidative damage in dopamine neurons, he will be able to see if the neurons’ telomeres are impacted and lead to a DNA damage response that could harm the cells.  

Ultimately, Dr. Burton will generate a special genetically modified zebrafish model that allows him to  damage the neuron telomeres directly and specifically, further investigating if telomere damage could be the reason that dopamine neurons die in PD. 

How does studying fish help further Parkinson’s research? 

Zebrafish share more than 70% of the same DNA as humans. They are a widely used animal model for neuroscience research. They are useful and effective for experiments for many reasons: 

• Their brain and nervous systems are functionally similar to humans, including the utilization of dopamine neurons. 

• They have telomeres similar to humans. 

• Genetic modifications can create zebrafish with transparent skin, allowing their brains to be studied directly under a microscope in an intact living animal. 

By exploring this innovative telomere-linked mechanism behind neuron loss in PD, Dr. Burton hopes to set the foundation for future therapies and treatments that bolster telomeres to help protect dopamine neurons and prevent disease progression.  

Speaking on his upcoming research, Dr. Burton said “This award provides a unique opportunity to develop a new collaborative program that we hope will help understand why brains cells malfunction and die in PD. As a clinician caring for patients with PD, this is an important goal, as it may eventually help us develop treatments that slow disease progression.” 

Meet more Parkinson’s researchers! Explore our My PD Stories featuring PD researchers.