Modeling tuberous sclerosis with organoids

Abstract

Single-cell profiling reveals a different path for the development of brain lesions

Abstract

Tuberous sclerosis complex (TSC) is a devastating disease characterized by distinctive tumors of the skin (angiofibromas), brain [cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs)], heart (rhabdomyomas), lungs [lymphangioleiomyomatosis (LAM)], and kidney (angiomyolipomas and renal cell carcinoma) ( 1 ). Neurologic manifestations can also include seizures and TSC-associated neuropsychiatric disorder, which encompasses aggressive behaviors, autism spectrum disorders, intellectual disability, and psychiatric disorders. TSC is caused by heterozygous germline mutations that inactivate TSC1 or TSC2, which normally inhibit mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 inhibitors are used for the treatment of brain, lung, and kidney tumors and seizures but do not improve all symptoms, and uncertainty persists about how brain tumorigenesis begins. On page 401 of this issue, Eichmüller et al. ( 2 ) identify a precursor cell that generates cortical tuber–like and subependymal tumor–like cells, increasing the understanding of neurological manifestations of TSC.