Epigenetic Control of Tet2 as a Mechanism Affecting PD Neuropathology
Abstract
The cells of our brain are able to change in response to signals we receive in our environment. The brain cells, known as neurons, exhibit plasticity, which refers to their ability to change at any age -- for better or worse. These changes in neuron plasticity are dependent on the precise control of genes. In Parkinson s disease, many genes are not turned on or off properly, which causes problems for the functions of brain neurons and enables the formation of deposits that are toxic to neurons. The death of neurons in certain brain areas in individuals with Parkinson s disease underlies the debilitating motor and cognitive symptoms of this illness. Since gene expression is key to the normal functions of neurons, our work aims to determine what causes the problems in gene regulation that leads to Parkinson s disease. Epigenetic mechanisms control gene regulation by placing "marks" on DNA, coating the DNA code. These marks determine when, for how long, and where in the body genes are to be turned on or off. Epigenetic marks also act like a volume dial for genes, determining how much a gene is able to be expressed. We recently performed a study that found that in the neurons of Parkinson s disease patients the epigenetic volume dial was turned way down, silencing many genes, including genes that, when inadequately expressed, contribute to the formation of toxic deposits in neurons. Importantly, one of the silenced genes in Parkinson s disease was a master regulator of epigenetic marks, TET2. TET2 is responsible for removing repressive epigenetic marks, which is a key factor in allowing normal neuron plasticity. The loss of TET2 in brain neurons creates havoc for the proper control of genes and could be centrally involved in the formation of toxic deposits that eventually kill neurons in the brains of Parkinson s disease patients. In the proposed study, we will carefully examine how TET2 is affected in neurons of the Parkinson s disease brain. We will extensively map the epigenetic changes at TET2 and definitively confirm whether the TET2 gene is silenced in Parkinson s disease neurons. For this, we use a method that provides precise information on exactly what epigenetic marks, on which piece of DNA, are defective in Parkinson s disease. We also look at the three-dimensional interactions of DNA to determine whether the architecture of DNA at the TET2 gene is abnormal in Parkinson s disease. Next, we use an animal model to determine how the lack of Tet2 affects the expression of genes that greatly increase the risk of Parkinson s disease. We also determine whether Tet2 loss leads to the presence of toxic deposits in neurons and causes neuron death, which would signify that TET2 has an important role in Parkinson s disease. This study deciphers the pathways implicated in the onset and progression of Parkinson s disease. This is the first study to determine the involvement of TET2 in Parkinson s disease. Our study will reveal new and important information on the primary causes of neuronal malfunction and toxic deposits in the Parkinson s disease brain. Furthermore, our study points to TET2 as a new target in creating more effective treatments for Parkinson s disease. This work will support the development and/or repurposing of modulators of TET2 (that are already becoming increasingly available for the treatment of other diseases like cancer) for the treatment of Parkinson s disease. One of these TET2-activating therapies includes vitamin C, which can be safely used as a preventative measure for individuals at risk of Parkinson s disease. Based on our study, if a treatment were to effectively augment TET2 activity in neurons, there is hope for the prevention and improved treatment of Parkinson s disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810512
Entities
People
- Viviane Labrie
Organizations
- United States Army
- Van Andel Institute