Investigating cAMP Modulation and Screening Bioactive Compounds as Therapeutic Options to Improve the Attention-Based Learning Deficiency in NF1
Abstract
Neurofibromatosis type 1 (NF1) is a genetic condition that affects 1 in 3,000 children and is mostly known because it causes light-brown patches of skin pigment, called caf?-au-lait spots, but also tumors that grow along nerves, called neurofibroma. A second aspect of NF1 is that the majority of children with NF1 show cognitive disabilities. The disorder is caused by mutations in a gene neurofibromin. In normal individuals, neurofibromin regulates the activity of another protein, called Ras, which controls cell divisions. In NF1 patients, the defective neurofibromin gene fails to regulate Ras, which then instructs cells to repeatedly divide, and this causes the formation of tumors. In contrast to the well-understood mechanisms by which mutant neurofibromin fails to regulate Ras and hence causes tumors to form, why and how mutant neurofibromin leads to cognitive disabilities is not well understood. Although the severity varies widely from patient to patient, the majority of children with NF1 (up to 70%) show cognitive impairment, including deficits in attention, the aptitude to learn new information, and the ability to recall information that is learned (i.e., memory). Through work in a zebrafish animal model of NF1, the long-term goals of our research program are to determine how neurofibromin regulates the ability of the brain to maintain attention, learn, and recall memories, and to identify new drugs capable of alleviating these distinct aspects of cognitive disability in NF1. The prevalent thought in the field has been that all cognitive deficits in NF1 patients are caused by the inability of neurofibromin to regulate Ras activity. However, it is well established that neurofibromin, the gene mutated in NF1, not only regulates the Ras protein, but several additional factors. One such factor is cyclic AMP, and we recently discovered that neurofibromin s regulation of cyclic AMP specifically mediates the brain s ability to learn new information, but is not needed to later recall that information (memory). Our work further showed that memory recall, but not the learning process, is governed by neurofibromin s regulation of Ras. This supports the idea that cognitive disability in NF1 is the product of distinct behavioral defects caused by the inability of neurofibromin to regulate distinct molecular factors. Consistent with this idea, our work showed that boosting cyclic AMP signaling specifically improved the NF1 learning defect and that inhibiting Ras exclusively restored memory recall ability. The first part of this proposal builds upon these findings to identify the types of brain cells where such cyclic AMP therapy should be targeted to improve learning and aims to further resolve the signaling factors by which neurofibromin and cyclic AMP control learning. Drugs currently being developed to alleviate cognitive disability in NF1 patients target the function of Ras and have not proved successful in clinical trials. Based on our new understanding of how neurofibromin regulates different factors to control distinct aspects of cognition, the most effective therapeutic strategy may be to improve specific behavior deficits with different drugs, which in combination will stimulate overall cognition. Hence, to alleviate cognitive disability in NF1, drugs specific for Ras to improve memory may need to be complemented with drugs that boost cyclic AMP to improve learning. It is also quite possible -- and likely -- that neurofibromin regulates additional factors to promote distinct types of cognition. Identifying these factors and their contribution to neurofibromin-regulated cognition has the potential to expose novel therapeutic targets. The zebrafish NF1 model provides an unparalleled system to easily screen thousands of drugs for their ability to improve learning and/or memory. Such drug screens in zebrafish have identified drugs now being tested in clinical trials for cancer treatment. Since the neurof
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1610091
Entities
People
- Marc Wolman
Organizations
- United States Army
- University of Wisconsin–Madison