Role of Neuronal Activity of Dopaminergic Neurons in the Substantia Nigra in Neuroprotection During Physical Exercise
Abstract
Patients diagnosed with Parkinsons disease (PD) suffer significant disabilities, which are centered on an inability to coordinate simple voluntary movements such as walking, speaking, and writing. According to the Parkinsons Disease Foundation, as many as one million Americans live with the disease and approximately 60,000 Americans are diagnosed with the disease each year. Additionally, ten million individuals are affected around the world, attesting to the devastating effects of the disease. These patients often present with movement abnormalities that can be extremely severe, preventing patients from performing their most basic day-to-day activities. PD results from the death of nerve cells in the brain responsible for secreting a chemical called dopamine (essential for coordinating voluntary movement) following the accumulation of a cell-destroying protein. The standard of care in treating PD patients centers on the dopamine replacement therapy, with dosage adjustment based on the severity of clinical manifestations. Unfortunately, this therapy often becomes ineffective in managing symptoms as more and more nerve cells are lost, calling for development of better therapies that can halt the destruction of nerve cells responsible for secreting dopamine. Studies have shown that physical exercise slows the progression of PD and protects dopamine-containing nerve cells from dying, but the exact mechanism of protection of dopamine-containing cells remains elusive. The goal of this project is to understand the precise mechanisms by which physical exercise prevents dopamine-containing nerve cells from dying and to develop a potential gene therapy that mimics the benefits of physical exercise using mouse models of PD. We will first determine the precise patterns of activity of nerve cells that secrete dopamine during physical exercise by recording electrical activity from those cells. Next, we will reproduce similar patterns of activity in the same cells by delivering a molecular tool that we developed. Our molecular tool is a combination of genes from a plankton and an algae and it can control the activity of nerve cells when biological light is generated upon injection of the activating drug into the animal. Since we have the ability to specifically control the activity of nerve cells that make dopamine, we will either block or activate them. With the blocking tool, we will ask if the benefits of exercise still remain even after blocking the activity of dopamine-containing nerve cells. With the activating tool, we will ask if such manipulation of nerve cells has beneficial effects similar to physical exercise. We hypothesize that the benefits of physical exercise are due to the increased activity of dopamine-containing nerve cells and that these benefits can be mimicked by our molecular activator. We have already collected plenty of preliminary data that support our hypothesis. Our study in mouse PD models will shed light on the mechanisms by which physical exercise alleviate symptoms of PD. In addition, our molecular tool will demonstrate the ability to halt the disease process responsible for PD, prevent the destruction of nerve cells that produce dopamine, and improve the symptoms of PD. Even though our study is strictly limited to mice, most of the relevant technologies used in this study, such as the method of gene delivery into the brain, are readily available in human patients. If successful, our findings will become the foundation for a novel gene therapy to treat patients affected with PD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910776
Entities
People
- Robert Elkan Gross
Organizations
- Emory University
- United States Army