The Contribution of Rapamycin-Insensitive Processes to Neurological Symptoms in TSC
Abstract
Neurological symptoms in tuberous sclerosis complex (TSC) such as epilepsy and TSC-associated neuropsychiatric disorders (TAND) have substantial impacts of the lives of individuals living with TSC. However, while medications such as sirolimus (rapamycin) and everolimus have revolutionized treatment of other manifestations of TSC, they have not been as successful in treating these neurological and behavioral symptoms. Therefore, there is a pressing need to understand the pathogenesis of TSC-associated epilepsy and TAND to develop novel treatments for both disorders, which is expressed in the Focus Areas of the FY20 TSCRP. TSC is caused by dysfunction of either the TSC1 or TSC2 genes, and in previous studies, we have identified changes in nerve cells that lacked TSC2. We then treated these nerve cells with rapamycin and found that many of the alterations that we found were not fully reversed, suggesting that there may be rapamycin-resistant processes in the brain that cannot be corrected with rapamycin analogs (rapalogs) such as sirolimus and everolimus. Notably, we determined that several of these changes could affect the formation or function of neural circuits. In addition, we have observed that rapamycin treatment later in neuronal development was unable to correct certain abnormalities, whereas earlier treatment was much more effective. Therefore, we formed the hypothesis that there are molecular processes in nerve cells that lack TSC1/2 that cannot be reversed with rapamycin treatment and that many of these processes emerge due to dysfunction early on in development. We plan to explore this hypothesis from three separate angles, and we will characterize rapamycin-resistant processes in human neurons, determine their contribution to alterations in neural connectivity, and explore their emergence throughout neurodevelopment. The ultimate goal of this research is to better understand the development of TSC-associated epilepsy and TAND and to reveal potential new therapies for these disorders. While this proposal represents fundamental research into the causes of neurological symptoms of TSC, we expect that it will have several impacts on the field of TSC research and patient care. The findings of this study will provide insights into the optimal timing of rapalog treatment and/or additional drugs that can target rapamycin-insensitive processes in nerve cells. If we are able to demonstrate that rapalogs are only effective at preventing important changes in nerve cells when treatment is begun early in development, then this would provide the impetus for testing early treatment of everolimus in at-risk individuals. In addition, the data generated by this research may lead to the identification of novel targets for the associated neurological disorders in TSC. In the long term, these strategies could be used to develop drugs that can be used in conjunction with conventional mTOR inhibitors for treatment of neurological symptoms in TSC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110209
Entities
People
- Mustafa Şahin
Organizations
- United States Army