The Surveillance Receptor TRPM2: A Novel Therapeutic Target for Rett Syndrome?
Abstract
Rett syndrome (RTT) is a devastating neurogenetic condition caused primarily by mutations of the gene encoding methyl-CpG-binding domain protein 2 (MECP2). RTT affects mostly girls, and symptoms appear early in life. Although the causal gene is now known, precisely how the loss of MeCP2 function leads to the severe impairments observed in both patients and experimental models remains poorly understood. Our work suggests a relatively unknown factor, known as TRPM2, may have as-yet-unrecognized role in RTT pathogenesis, and importantly that it may represent a target for therapeutic intervention. Under normal circumstances, TRPM2 is largely silent in the brain and only becomes active when the brain is stressed. In the brain of RTT patients, there is almost a constant state of stress. In addition, one of the normal functions of MeCP2 is to repress gene expression, and TRPM2 is one of its targets. In brain tissue lacking MeCP2, we find the expression of TRPM2 to be significantly elevated above normal levels. These observations led us to hypothesize that there would be too much TRPM2 activity in the RTT brain and that diminishing its activity would be beneficial. To begin testing this hypothesis, we generated RTT mouse models that lack half of their normal TRPM2. Excitingly, we found many RTT-like aspects of these mice were improved compared to regular RTT mice. We then looked to see if cellular deficits in the MeCP2-deficient brain would also be improved in the RTT mice lacking half of their TRPM2. Consistent with the improvements seen in behavior, key signaling systems thought to contribute to RTT pathogenesis were significantly improved. While these initial results are exciting, our initial study did not look at all the cardinal RTT-like deficits present in these mice that mirror problems encountered by patients nor did it identify the mechanisms through which the decreased level of TRPM2 afforded the observed benefit. This study is designed to address these key areas of need. We believe that we have identified an important contributor to RTT pathogenesis, and this knowledge will help the field better understand how RTT develops. What is also needed is a drug that can be used in patients to block TRPM2. At present, no such drug exists. To address this need, we will initiate a drug development effort to engineer new drugs that target TRPM2 as the first step towards obtaining a TRPM2 drug for use in patients. We believe our work has identified an important player in RTT, and importantly one that could be targeted for developing RTT treatment strategies. This project addresses key issues to move this possibility forward and expand the knowledge of how MECP2 mutations cause a debilitating condition in children.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010729
Entities
People
- James Eubanks
Organizations
- United States Army
- University Health Network