Mutations in the two genes that cause the disease tuberous sclerosis complex, or TSC, interfere with the normal formation of axons, the long and thin strands that conduct electrical signals between brain cells, researchers contend in a report in Genes and Development.

The paper also shows that in mouse models of TSC, the cancer drug rapamycin can normalize axon formation, providing further evidence for its potential as a treatment for TSC and autism.

TSC is a rare disorder that is characterized by the presence of benign tumors all over the body; about half of all individuals with TSC are on the autism spectrum.

Mutations in the TSC1 or TSC2 genes have been known to cause the disorder for over a decade, but not much is known about the biological mechanism that causes these mutations to wreak havoc in the brain.

In the study, researchers used genetic engineering techniques to both suppress and over-express TSC1 and TSC2 in embryonic mouse brain cells.

“TSC 1 and TSC 2 are crucial,” says Mustafa Sahin, a neurobiologist at Children’s Hospital Boston and a member of the research team. “If you don’t have TSC1 or TSC2, you get multiple axons, not one axon. And if you over-express TSC1 or TSC2, you don’t get an axon at all.”

These multiple axons may be what’s causing the characteristic benign tumors — called tubers — and the abnormally shaped ‘giant cells’ in the brains of people with the disease, Sahin says.

Previous research on the role of TSC genes had focused on later stages of brain development, when synapses form.

“What’s exciting here is that these researchers looked earlier in development, to see what function TSC1 and TSC2 had just after the neurons were born,” says neuroscientist Jill Wildonger of the University of California, San Francisco.

That’s important for individuals with the disease, she says, because their tubers probably form during these earlier stages.

“We’re now better understanding the function of TSC1 and TSC2 at multiple stages in neural development,” Wildonger says. “All of these factors along the way affect how neurons communicate with each other — or miscommunicate.”

…Read the rest of my latest piece at SFARI