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The current idea about how tuberous sclerosis occurs places mTORC1, a protein complex that regulates cell metabolism, as the major driving force behind the disease. But according to a new study published in the Proceedings of the National Academy of Sciences U.S.A. by researchers at Baylor College of Medicine and Texas Children’s Hospital, the development of this rare condition also involves a second mechanism that is independent of mTORC1. The findings can potentially lead to new treatments that might benefit patients who partially respond to current therapies focused on mTORC1.

“Tuberous sclerosis is a rare genetic disease that causes benign tumors to grow in the brain, kidneys, skin and other organs. Patients present with a combination of symptoms that can include seizures, developmental delay, skin abnormalities and kidney disease,” said first and co-corresponding author Dr. Rituraj Pal, postdoctoral associate of molecular and human genetics at Baylor.

Tuberous sclerosis is caused by mutations in the genes TSC1 and TSC2. The current thought is that the dysfunctional proteins produced by these mutated genes fail to regulate mTORC1, which then becomes hyperactive and leads to the development of the disease. How the disease actually develops is still not clear.

“Previous studies have associated tuberous sclerosis with excessive accumulation of glycogen, a main source of energy, inside cells, although this has not been clearly shown,” said corresponding author Dr. Marco Sardiello, assistant professor of molecular and human genetics at Baylor and a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. “We know from other conditions that glycogen accumulation damages cells.”

Cells are like homes. Both are constantly producing waste that must be disposed of to keep a healthy, functional environment. Even materials that are usually not toxic, such as glycogen, will become so if they accumulate inside the cell. To gain insights into how the disease happens, the researchers first investigated whether glycogen accumulated inside cells with the disease.