My lab focuses on how genes important in the pathobiology of select human neurologic diseases, are regulated at a post-transcriptional level. Once produced by transcriptional activation, coding mRNA levels fluctuate in response to environmental cues through changes in their rate of decay. Decay is typically controlled through complex interactions between embedded sequence and/or structural information intrinsic to the mRNA and recognition proteins. The latter often recognize nascent mRNAs in the nucleus through these sequence cues and participate in the transport, localization, translation and ultimate decay of specific mRNAs in the cytoplasm. Dysregulation of any of these processes can alter the levels of protein produced with compromise of cell function.

Currently we study 2 important clinical problems: alzheimer’s disease (AD) and fragile X mental retardation syndrome (FXS). In AD, the overproduction of beta-amyloid (A beta) causes neurons to die. A beta is cleaved from the larger amyloid precursor protein (APP). In the brains of some AD patients, excess APP mRNA is present. We are studying how APP mRNA levels are controlled by changes in decay with the goal of understanding the process at the molecular level. We have identified 2 regions of the mRNA which interact with multiple proteins to determine how much APP mRNA is present and how much APP and A beta are produced. We plan on testing whether A beta production can be reduced by accelerating the decay of APP mRNA.

In FXS, the loss of a single gene (fragile X mental retardation protein, FMRP) causes mental retardation. FMRP is an RNA binding protein whose functions are poorly understood. We have recently identified a critical synaptic protein called PSD-95 whose activity dependent production is controlled by FMRP. Our goals are to identify where FMRP interacts with PSD-95 mRNA, how cell activation changes that interaction and how the cellular machinery mobilizes PSD-95 mRNA to translating ribosomes. Thus we utilize the powerful tools of molecular biology, genetics and biochemistry to understand the regulation of critical neurologic disease related genes.