An Interspecies Approach to Model Differential Cognitive Effects of Specific Neurofibromin I Mutations
Abstract
Neurofibromatosis 1 (NF1) is characterized by highly variable symptoms that may or may not include concurrent tumors and cognitive deficits. However, the majority of patients present a degree of cognitive deficits, as one recent study of 81 NF1 children found that >80% had moderate to severe cognitive impairment. Although NF1 associated cognitive symptoms do not progress with age, cognitive dysfunction leading to behavioral problems and school failure is the most common problem affecting quality of life in children with NF1, and patients and their families often perceive it as among the most serious manifestations of this disease. However, what underlies NF1-associated cognitive dysfunction remains poorly understood, and the disease is difficult to be studied in humans; most progress to date has come from research on two animal models, the fruit fly Drosophila and the mouse. In both organisms, loss of their Nf1 genes results in cognitive deficits, but the molecular reasons behind them have remained unclear, which hampers targeted pharmaceutical amelioration and improvement of the lives of children and adults diagnosed with the disease. We have focused on understanding the mechanisms of cognitive impairment in Nf1 using the fruit fly as a model and have made a crucial discovery regarding an ameliorative drug that reduces the activity of a protein that activates the molecular cascade that requires Nf1. In this application, we focus on modeling mutations that are highly linked with cognitive disabilities and less with tumors in patients. We try to understand the reason behind the highly variable cognitive deficits in patients; to do this, we plan to generate new fly and mouse models bearing mutations on the Nf1 gene typically found in patients presenting cognitive deficits. We aim to elucidate molecular mechanisms that are differentially affected by these mutations which, in the fly model, do not respond to the pharmacological treatment mentioned above. We hope that, if funded, our work will lead to a significantly better understanding of these largely atypical Nf1 mutations, which nevertheless are not uncommon and present patients with serious cognitive defects. Moreover, we hope that the models we will generate will help us understand the notorious variability of behavioral clinical manifestations of the disease, as well as explore translational avenues toward pharmaceuticals that will ameliorate disease symptoms and ease the burden of cognitive dysfunction in affected children and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010255
Entities
People
- Efthimios Skoulakis
Organizations
- Alexander Fleming Biomedical Sciences Research Center
- United States Army