Hyperactive signaling of the protein complex mTORC1 has long been linked to a group of brain disorders that includes tuberous sclerosis complex and hemimegalencephaly, characterized by childhood seizures. Now, Yale researchers led by Angélique Bordey, Ph.D., professor of neurosurgery and of cellular and molecular physiology, have revealed new details on how overactive mTORC1 actually changes brain development.
The scientists observed the placement of brain cells as mouse embryos developed and studied the effects of changing mTORC1. As expected, hyperactive signaling of the protein complex led to malformations in one area of the brain. Since mTORC1 affects many different cellular processes, they then altered different associated processes one at a time, testing whether each was responsible for the malformations.
Changing levels of one group of downstream proteins, 4E-BPs, was enough to disrupt the brain formation in a way similar to mTORC1. Moreover, restoring normal signaling of 4E-BPs prevented the effects of overactive mTORC1, the researchers reported Sept. 19 in Proceedings of the National Academy of Sciences, pointing toward a potential drug target to treat or even prevent the seizure disorders.