Scientists uncover cellular mechanism behind rare childhood brain disorders

Thousands of times per year, a family's moment of joy turns to unexpected grief. A seemingly healthy infant stops smiling or making eye contact. Their limbs grow weak. The tiny child suffers seizures and breathing problems.

Jawdat Al-Bassam, an associate professor of molecular and cellular biology at the University of California, Davis, often hears from these families. "I've gotten emails from folks all over the world," he said.

"The parents are asking if there's a way to do gene therapy," Al-Bassam said. These life-shortening diseases, with names like infantile encephalopathy, corpus callosum hypoplasia and Kenny-Caffey syndrome, currently have no treatments. But Al-Bassam and his team have made a major discovery that could change that.

In addition to enabling new treatments, this discovery could help scientists identify dozens of other genetic diseases in which children experience various neurological problems with no clear explanation.

Cellular skeletons guide neural connections

Al-Bassam studies structures called microtubules, which form protein skeletons inside cells. As a cell grows and changes shape, its cytoskeleton drives the process – lengthening its scaffold of microtubules.

"They are the cell's force generators," Al-Bassam said. These telescoping structures are crucial in the developing nervous system.

They help nerve cells grow the long tendrils, called axons, that connect with other nerve cells. These axons allow neurons to communicate across long distances - especially in the optic nerves that connect the eyes to the brain, in the corpus callosum that connects the left and right hemispheres of the brain, and in the long nerves that reach down to the arms, legs, lungs and other organs.

But this process can easily go awry, with terrible consequences.

If the tubulin cofactors malfunction, it reduces the cell's supply of αβ-tubulin, disrupting the microtubules that guide neuronal growth. "Even a small percent decrease in αβ-tubulin supply is toxic to the cell," Al-Bassam said.

Devastating disorders of unknown origins

"Some of these mutants were identified almost 35 years ago in yeast," Al-Bassam said. They were discovered 15 years later in humans. But the delicate proteins were difficult to study, he said, "so this whole field of research was essentially shelved for a long time."

These experiments were led by Aryan Taheri, a former UC Davis undergraduate who was working in Al-Bassam's lab at the time; Taheri has since graduated and is now pursuing a Ph.D. at UC Berkeley. "He's extremely talented," Al-Bassam said. "We look forward to seeing more amazing work from him in the future."

These discoveries won't immediately lead to treatments, but they could offer hope to affected families, Al-Bassam said: "For the first time, we have a precise picture of exactly what's going wrong, and what a future therapy would need to fix."

They could also allow disorders to be diagnosed more quickly. Today, families often endure a diagnostic odyssey in which the genomes of parent and child are sequenced in search of a mutation that might explain the problem – often yielding inconclusive results. A clearer understanding of which mutations disrupt the function of tubulin cofactors could lead to quicker diagnosis.

"Many children are born with minor, unexplained neurologic disorders," Al-Bassam said. "Some of them may turn out to have small changes in these genes. Finding that out would be a huge step forward."

Al-Bassam's research is funded by the National Institutes of Health. His team's research on αβ-tubulin biogenesis utilized advanced scientific facilities at UC Davis, including the Biological Electron Microscopy Campus Core and the High Performance Computing Core.

Source:

University of California - Davis

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