Scientists have discovered a new function for a protein complex at the heart of Bardet-Biedl syndrome, or BBS, a human genetic condition for which there is presently no therapy.

When the BBSome protein complex fails, Bardet-Biedl syndrome develops. BBS has been classed as a disease of the cilia because the BBSome governs the development and function of cilia, the hair-like structures on the surface of cells.

However, the vast range of symptoms associated with BBS—the most prevalent of which is eyesight loss, as well as obesity, additional fingers or toes, and kidney dysfunction—has led to speculation that the syndrome’s etiology may not be limited to the cilia.

In a new study published in Developmental Cell, a group of researchers from the University of Michigan Life Sciences Institute gives the first direct proof that these ideas are true. Their findings show that, at least in one popular model species, the BBSome functions outside of cilia to promote vision.

Experts in the lab of LSI faculty member Shawn Xu were exploring how microscopic roundworms called Caenorhabditis elegans can feel light despite lacking eye-like structures when they made the discovery. The Xu group employs C. elegans as a model to investigate the fundamental biology behind diverse forms of experience since they have a simple and well-mapped neural system.

To locate the genes involved in the worms’ capacity to respond to light, the scientists used a genetic screen, which involves introducing random mutations to see which genes are required for a certain biological function. The majority of the mutations that caused worms to lose their ability to detect light were found in the BBSome. The worms with BBSome mutations also lost their capacity to feel light as they aged, similar to how BBS sufferers lose their vision over time.

The team determined that the BBSome is involved in light sensing in addition to its role in the cilia in a series of additional studies. They altered C. elegans to eliminate all cilia in one scenario; in another, they left the cilia on the worms but prevented the BBSome from reaching the cilia. The worms were still able to detect light in both circumstances as long as the BBSome functioned in the rest of the cell.

“”It’s a great demonstration of the power of model organisms,” said Xinxing Zhang, the study’s main author and a postdoctoral researcher in the Xu lab. “Cilia are essential for most organisms. But we can remove cilia from the C. elegans and they still survive, allowing us to uncover this unexpected role for the BBSome completely independent of the cilia.”

C. elegans perceive light through a receptor protein called LITE-1 that lies on the surface of neurons and transmits signals to the central nervous system to respond to the light (in the worms’ case, by migrating away from it), according to prior research from Xu’s team.

In this latest study, the team found that when BBSome goes wrong inside the cell, LITE-1 receptors are pulled back into the cell from the surface and then broken down. This stops the worms from being able to sense light.

The scientists revealed that the process of decomposing LITE-1 is controlled by another protein called DLK in a second genetic screen. DLK is prevented from initiating a chain reaction that incorrectly breaks down LITE-1 by the BBSome.

In humans, both BBSome and DLK are conserved, and the researchers were able to show that BBSome inhibits DLK production in human cells in a comparable way. They hypothesize that the BBSome–DLK–photosensor pathway is responsible in the visual loss that is so common in Bardet-Biedl Syndrome patients.

“Because BBS is known to be caused by defects in the BBSome, there has been a longstanding assumption that the disorder must be tied to the cilia,” noted Xu, who is also a professor of molecular and integrative physiology at the University of Michigan Medical School. “We are not disputing that BBS is tied to defects in the cilia. We are just offering direct evidence that the BBSome can also function outside of cilia, and it has a role there related to light sensation. Perhaps this can broaden the view of how to develop treatments for BBS.”

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