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2011 Grants - Sloane
Double Stranded RNA Receptor Function in Neurofibrillary Tangle Formation
Jacob Sloane, M.D., Ph.D.
Beth Israel Deaconess Medical Center
2011 New Investigator Research Grant
The protein tau normally plays a vital role in maintaining the structure and function of nerve cells. Tau is modified by a process called phosphorylation, or the addition of phosphate molecules. In Alzheimer's disease, however, tau molecules become excessively phosphorylated. Such "hyperphosphorylated" tau takes on an abnormal shape and loses its ability to carry out normal functions. Abnormal tau eventually clumps together into neurofibrillary tangles that hinder cell-to-cell communication in the brain. This tau pathology leads to cognitive decline in Alzheimer's and another neurological disorder called frontotemporal dementia.
An enzyme known as protein kinase R (PKR) becomes activated when brain cells undergo stress. Like tau, PKR is also modified by phosphorylation. Recent studies have found that PKR is associated with brain cells bearing hyperphosphorylated tau in Alzheimer's disease. This enzyme has also been shown to modulate the phosphorylation of tau, but it is unknown whether PKR plays a role in creating abnormal tau and neurofibrillary tangles.
For this grant, Jacob Sloane, M.D., Ph.D., and colleagues plan to assess the links between PKR and toxic tau in Alzheimer's-like mice. Specifically, they will determine if PKR regulates tau phosphorylation in the mice or if the removal of PKR reduces the animals' abnormal tau levels. They will also assess whether toxic PKR is linked to a disease-related type of ribonucleic acid (RNA). RNA molecules help produce proteins from genes, and they are normally shaped like a single, long strand. Certain RNA molecules that produce viruses and other harmful compounds, however, have a double-stranded shape. Based on previous findings, Dr. Sloane and colleagues believe that PKR is activated by double-stranded RNA (dsRNA). To test this hypothesis, they will determine whether dsRNA accelerates tau phosphorylation in mice with and without PKR. The results of these research efforts could shed new light on the mechanisms underlying tau pathologies in dementia.