Rev-ERBa Regulation of Dopaminergic Neuroplasticity and Impact on Neurodegeneration
Abstract
Parkinson s disease is a neurological disorder characterized by several motor symptoms. More than one million Americans suffer from the disease. The exact causes of the disease are not fully understood. Those serving in the armed forces are at a particularly high risk for Parkinson s disease. This is because of a combination of factors. Deployed military personnel are exposed to a number of chemical compounds, such as nerve gases and herbicides, that greatly increase the risk of developing Parkinson s later in life. In addition, traumatic injuries to the head, such as concussions, have also been linked to the development of the disease. In Parkinson s disease, the major symptoms are caused by degeneration of a very specific type of nerve cell in the brain called the dopamine neuron. These cells gain their name from their unique ability to produce the chemical dopamine, a type of signaling molecule called a neurotransmitter. In our lab, we found that a protein called REV-ERB-alpha, which is highly active in these nerve cells, in a mouse model of Parkinson s disease. We and others have found that this protein is critical for preventing these nerve cells from making too much dopamine, which can be toxic to the cells. When this protein is overactive, however, it prevents these cells from functioning normally. As the dopamine neurons degenerate in Parkinson s disease, the motor symptoms of the patient get worse. Part of the reason for this is that a process called neuroplasticity is impaired. Broadly, neuroplasticity is the ability of neurons to form new connections with other nerve cells. It is neuroplasticity that allows the neurons in the brain to compensate for damage. Enhancing neuroplasticity in dopamine neurons has been shown to be an effective means of reducing symptoms in models of Parkinson s disease. It is therefore a promising line of research with great potential therapeutic benefits. There is to date, however, no efficient and precise way of enhancing plasticity in dopamine neurons. We hypothesize that by changing REV-ERB-alpha activity, we would be able to change the neuroplasticity in dopamine neurons. By doing so, we would be able to improve the function of these cells and make them more resilient. We will test our hypothesis in a novel cell culture model that allows us to grow human dopamine neurons in the lab. These are the exact cells that degenerate in Parkinson s disease. In these cells, we can then change REV-ERB-alpha activity with specific drugs and determine the effect on the health of dopamine neurons. We will also study how these drugs change the neuroplasticity of these neurons. We will also assess whether changing REV-ERB-alpha activity can be protective in models of Parkinson s disease. This will be done using state-of-the-art high-throughput technologies, which will allow us to collect and analyze large sets of data to get a very clear picture of the role and mechanisms of this protein in Parkinson s disease. As we will be using existing drugs that are known to change REV-ERB-alpha activity and we will be studying their effect on the exact human cells that degenerate in Parkinson s disease, this project will have high clinical significance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810486
Entities
People
- Benjamin Kolisnyk
Organizations
- The Rockefeller University
- United States Army