Exosome Contribution to Social Deficits in TSC
Abstract
Children with the genetic disorder tuberous sclerosis complex (TSC) exhibit seizures and a range of neurological disabilities. There is no cure or treatment for the neurological deficits, including cognitive deficits and autism. We and others have contributed to significant advances toward understanding the etiology of epileptic seizures in TSC, providing novel therapeutic options. Seizures arise from the presence of mutant neurons forming focal cortical malformations, called cortical tubers, that are present in almost all individuals with TSC and occur as a result of somatic mutations during embryonic life. But the mechanisms leading to autism remain unknown, and many grave behavioral manifestations such as seizure worsening or abrupt occurrence at any age have no explanation. We hypothesize that the TSC mutant neurons release nanovesicles, called exosomes, containing abnormal, detrimental signals. These are then taken up by surrounding healthy neurons, progressively altering the function of the wild-type cells and causing autistic traits and worsening of seizure activity. Exosomes are released by all cell types, including neurons, and transfer molecules like proteins and RNA from cell to cell. We will test this hypothesis in novel mouse models of focal cortical tubers leading to seizures that worsens over time or social deficits even in the absence of seizures. We will investigate whether injecting exosomes collected from mutant neurons into seizing mice worsens seizures while reducing exosome release prevents seizure worsening. To reduce exosome release, we will decrease the level of Rab27a, which controls exosome release. Similarly, we will examine whether injecting “diseased” exosomes into wild-type mice leads to social deficits while reducing exosome release after birth prevents the establishment of social deficits in non-seizing mice that contain mild focal cortical tubers. If reducing exosome release after birth by decreasing Rab27a level alleviates social deficits as hoped, using gene therapy to decrease Rab27a in humans would provide the first therapeutic option in TSC individuals to reduce social deficits and thus autistic traits.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010120
Entities
People
- Angélique Bordey
Organizations
- United States Army
- Yale University