We have recently identified a new type of molecular pathology in AD that develops in concert with neurofibrillary tangles, which are one of the hallmark pathologies of Alzheimer’s disease (AD). Neurofibrillary tangles form from clumping of tau protein, and occur as nerve cells deteriorate. In the Wolozin lab, we have discovered that a class of proteins, termed RNA binding proteins, clump alongside the tau protein and constitute a new type of pathology in the AD.
This new pathology is important for three reasons. 1) it appears to cause some of the tau pathology that occurs in AD; 2) the RNA binding proteins sequester mRNA transcripts as they clump, which interferes with the normal functions of the nerve cells in our brain; and 3) there are potentially new pathways that regulate RNA binding proteins, and can be targeted for pharmacotherapy in AD.
The research in the proposal focuses on understanding how the pathological clumping of these RNA binding proteins interferes with the process of protein synthesis as mRNA is translated into protein, and thus interferes with the functioning of nerve cells. The first part of the proposal will be to determine the extent and location of deficits in protein synthesis in the Alzheimer brain. The second part of the proposal will identify the exact mRNA transcripts that are sequestered by the RNA binding protein/tau complexes; this will possibly allow us to develop treatments or diagnostics targeted to the specific mRNA transcripts and proteins that are lost in disease.