Dysregulation of RNA Transport Granules in the Pathophysiology of Fragile X Syndrome
Abstract
Fragile X Syndrome (FXS) is the most common cause of inherited mental deficiency in humans and is conservatively estimated to affect about 1:7,000 male and 1:11,000 children from all ethnic groups worldwide with males being much more severely affected. Approximately 40% of individuals with FXS are also autistic. While life expectancy is normal, FXS is characterized by developmental delay and significant intellectual disability. Boys with FXS have an average IQ of ~50 (including problems with attention and anxiety) while the general population has an average IQ of ~100. In addition to a negative impact on patient health and well-being, FXS is a significant psychosocial and financial burden on caregivers and the healthcare system as a whole. Despite being first described over 50 years ago, there still is no cure or FDA-approved treatment for FXS. Collectively, this highlights the need to focus research efforts on understanding more about what causes FXS in humans. Historically, FXS has been diagnosed by looking for a particular mutation (called a “triplet expansion”) in the FMR1 gene that prevents it from making a protein called FMRP. The FMRP protein has important functions in the regulation of the development of neurons in the brain. In particular, the FMRP protein helps to make and maintain connections (called “synapses”) between neurons. If these synapses are not created correctly, then signals in the brain may not be transmitted correctly. The focus of most research into FXS has been on the how FMRP is controlling the production of other important neuronal proteins involved in synapse formation and function. These processes are occurring at synapses that can be relatively far away from main “cell body” of the neuron. The work presented in this grant proposal is innovative in that it is instead focusing on how the FMRP protein gets to synapses and whether it brings with it the template for protein synthesis (called “RNA”). This is an understudied area of research in the FXS field. Current work into this area suggests that FMRP assembles with RNA into a semi-solid structure called a “granule.” These granules interact with another protein that acts like a molecular “motor” that physically pulls the granule towards the synapse. This grant proposal takes advantage a different type of mutation in the FMR1 gene that does not prevent FMRP from being made but instead alters its function. These mutations have been linked to several severe cases of FXS. Preliminary data is presented in Drosophila melanogaster (aka “fruit fly”) cell line suggesting that these mutations alter the ability of FMRP to properly form granules in cells. The primary goal of this proposal is to determine if similar results are observed in Drosophila neurons in the living organism and in neurons that have been removed and grown in a culture dish. The hypothesis being tested is that these mutations will prevent granules (containing FMRP and RNA) from being transported correctly towards synapses. The proposed work is technically innovative because experiments will use an array of cutting-edge microscopy techniques to analyze the structure and properties of granules. In terms of impact, Drosophila has been a well-established model system used to study FXS for about 30 years. Flies are genetically simpler than mammalian FXS models, have a significantly shorter lifespan, and there are many more tools available in Drosophila to study gene function. It is an ideal system in which to test high-risk/high-reward hypotheses before moving into more complex model organisms. One predicted outcome of this proposal is expected to be the generation of a sufficient amount of preliminary data that can used to obtain funding at the level of a NIH Research Project Grant (R01) in order to study these processes in mammalian FXS models. In the much longer term, data generated by these studies are expected to identify these processes as novel cellular and molecular targets for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110026
Entities
People
- Scott Barbee
Organizations
- United States Army
- University of Denver