Dissecting the Molecular Causes and Consequences of Synaptic Dysfunction in Fragile X Syndrome
Abstract
Fragile X Syndrome (FXS) is a genetic condition that causes intellectual disability, behavioral and learning challenges, and various physical characteristics, such as long and narrow face, large ears, and unusually flexible fingers. The affected children usually fall behind many developmental milestones and may additionally display sensory issues and seizures. FXS is the most common inherited cause of intellectual disability and the leading single-gene cause of autism; it occurs nearly as commonly as muscular dystrophy or cystic fibrosis. Despite intensive research efforts, there are still no known cures or medicines approved for treatment of FXS, which continues to present a substantial burden to the lives of patients and their families. Although FXS is clinically a complex disorder, it is caused by failure of a single gene to produce protein, called FMRP, that is necessary for normal brain function. The monogenic origin of the disorder has facilitated studies of FXS in animal models, including mouse, zebrafish, and fruit fly, where FMRP deletion recapitulates several clinical features of FXS. In fact, much of our knowledge about the function of FMRP in the brain has been learned from animal studies. This includes the insights about its impact on neuronal connectivity or, more precisely, synaptic signaling, which is thought to be the key process affected in FXS. Importantly, several pharmacological attempts to restore synaptic signaling in animal models have successfully normalized many symptoms of FXS, providing a reason for optimism that similar approaches could be taken to treat patients with FXS. However, the latest clinical trials have not shown significant improvement of symptoms associated with FXS, suggesting that the results from animal studies are not directly transferrable to humans and that better understanding of the condition in humans is required for the development of effective therapies. In this proposal, a new platform will be established that will address two of the most pressing unmet needs in the research of FXS: (1) studies on human neurons and (2) a system for rapid evaluation of synaptic function. This platform will be based on a micropatterned solid support and will bring together several recently developed technologies in molecular and cellular biology, including optogenetics, genome editing, stem cell technologies, and neuronal differentiation protocols. As a whole, the platform will allow for directed growth of FXS patient-derived neurons and for monitoring of changes in their synaptic signaling in response to genetic and pharmacological perturbations. The proposed and future studies based on this platform will identify the key molecular underpinnings of FXS in humans and will have immediate implications for the development of therapies for this devastating disorder. This research idea presents a novel concept and a significant advantage over the previous studies of FXS primarily because it will enable a direct scrutiny of the core pathological process of the disorder -- defects in neuronal connectivity. As such, the platform established herein will be ideally suited for the identification and testing of novel drug targets, as well as for the development and evaluation of novel and existing therapeutics for the treatment of FXS. Given that synaptic dysfunction is a common pathological feature in humans, the proposed platform will also serve as a basis for future studies of several related neurological disorders, including different forms of intellectual disability and autism spectrum disorders.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710220
Entities
People
- Jernej Murn
Organizations
- United States Army
- University of California, Riverside