Targeting the Neurospecific Adenylyl Cyclase in the Treatment of Fragile X Syndrome
Abstract
Fragile X syndrome (FXS) represents a major form of heritable intellectual disability that is caused by mutations in the FMR1 (fragile X mental retardation 1) gene, which encodes a protein named as fragile X mental retardation protein (FMRP). In addition to intellectual disability, FXS patients also display a pleotropic neurological defects, including seizure, hyperactivity, repetitive behavior, and impaired social interaction, all of which result from the loss of functional FMRP. In particular, FXS is also a leading genetic cause for autism. Currently, there is no efficacious medical treatment for FXS. The current conception of therapeutic strategies is mainly based on: (1) FMRP is an RNA binding protein and its mutation may lead to abnormal protein synthesis and (2) lack of FMRP causes overactivation of intracellular signaling molecules, some of which are stimulated by multiple Gq-coupled receptors and may in turn cause exaggerated protein synthesis. We recently identified a novel target of FMRP that plays intricate roles in synaptic signaling, whose mRNA translation in the brain is negatively regulated by FMRP. Consequently, in the absence of FMRP, the enhanced translation of this FMRP target causes overactivation of the PI3K/ERK1/2-S6K1 intracellular signaling cascade. Strikingly, genetic reduction of this FMRP target in FXS mouse model corrects the aberrantly elevated PI3K/ERK1/2-S6K1 signaling and multiple cellular and behavioral abnormalities, indicating that this FMRP target may play prevailing roles in FXS pathology. By using molecular, cellular, and behavioral experimental approaches, we propose to determine: (1) how FMRP regulates the translation of this target, (2) whether and how genetic reduction of this FMRP target normalizes the exaggerated intracellular signaling, protein synthesis, and altered synaptic function in FXS neurons, and (3) whether and how acute inhibition of this FMRP target by a Food and Drug Administration-approved drug attenuates aberrant signaling caused by FMRP deficiency in mouse neurons and human neurons derived from induced pluripotent stem cells (iPSCs) and FXS phenotypes in the Fmr1 knockout mouse. We expect that the successful completion of this project will fill an important knowledge gap regarding how alteration of FMRP-regulated translation leads to the overactivation of intracellular signaling. Furthermore, answers to the questions raised in this proposal may help to develop a novel mechanism-based and practical therapeutic treatment for FXS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710270
Entities
People
- Hongbing Wang
Organizations
- Michigan State University
- United States Army