Novel Mechanism for Death of Dopaminergic Neurons in a Model for Parkinsonís Disease
Rapid Response Innovation Awards, 2014
Study Rationale: † † † † † † † † ††
Parkinsonís disease (PD) is due in large part to the death of dopaminergic neurons in a part of the brain called the substantia nigra. An understanding of why, as we get older, these cells die while other cells live is critical to learning how to prevent their death and to treating PD. The cells that die give signals to the brain in part through pores or channels that open on their surface and allow the entrance of potassium. A protein that puts phosphates on proteins, thus controlling their activity, is increased in the blood of pre-clinical models that develop Parkinsonís. This protein appears to tightly stick to the potassium pore, which †might prevent it from allowing potassium to enter the cell and which could contribute to the death of the cell and the development of PD.
We will determine if the protein that accumulates in the blood of PD models prevents the opening of the potassium pore in dopaminergic neurons and whether a small molecule that interferes with this protein will restore the function of the pore and prevent the death of dopmaninergic neurons.
To determine whether the potassium pore opens normally in dopaminergic neurons of models that develop Parkinsonís disease, we will cut slices of brain and identify the cells at risk for cell death. Using small glass tubes, we will measure the flow of potassium into these cells. This will allow us to determine whether the pores are present and if they work normally. In another set of models we will treat with the small molecule inhibitor and determine if this inhibitor prevents the loss of function of the pore. Since many of the cells die, we will we will determine if the inhibitor prevents the cells from dying as the model gets older and develops the disease.
Impact on Diagnosis/Treatment of Parkinsonís Disease: † † † † † ††
If we find that the potassium pore is not working in the nerve cells of the models with Parkinsonís and that the small molecule inhibitor prevents this, it will become important to understand why this might cause the nerve cell to die and to develop tests for the abnormal protein in the blood of patients. This may help identify early stages in the development of Parkinsonís disease and might help identify new targets for the prevention of the progression of the disease.
Next Steps for Development:
If these studies identify a protein that prevents the potassium pore from functioning in the brain, we will determine whether it causes the cells to die. Then we will determine if brains from patients with Parkinsonís disease contain this protein stuck to the potassium pore. Since some blood cells also contain this potassium pore, we will develop a method to detect whether the two proteins are associated in the blood as a method of predicting the likelihood of such an association in the brain and early onset of abnormal function and death of dopaminergic neurons.
Professor of Medicine and Physiology at Tufts Medical Center; Tufts University School of Medicine
Location: Boston, Massachusetts, United States