Roundworms offer new insights into Bardet-Biedl syndrome

Roundworms offer new insights into Bardet-Biedl syndrome

Scientists have identified a new role for a protein complex at the center of a human genetic disorder called Bardet-Biedl syndrome, or BBS, for which there is currently no cure.

Bardet-Biedl syndrome occurs when certain BBS proteins are defective. Because the BBSome regulates the shape and function of cilia, which are the hair-like structures on the surface of cells, BBS has been classified as a disease of cilia.

But the wide spectrum of symptoms associated with BBS – the most common of which are vision loss, as well as obesity, enlarged fingers or toes and kidney dysfunction – has led to the hypothesis that the cause of the syndrome may not lie solely within the cilia.

In a new study published in developmental cell, a team from the University of Michigan Life Sciences Institute is now providing the first known direct evidence for these hypotheses. Their findings show that the BBSome acts outside the cilia to support vision, at least in one common model type.

The discovery began when scientists in LSI faculty member Shun Zhou’s lab were investigating how tiny worms called Caenorhabditis elegans sense light despite having no eye-like organs. Because C. elegans has a simple and well-defined nervous system, the Xu lab uses it as a model for understanding the basic biology behind the various forms of sensation.

The team performed genetic screening, the process of introducing random mutations to identify genes required for a particular biological process, to find genes involved in the worms’ ability to respond to light. It turns out that most of the mutations that caused the worms to stop sensing light were in the BBSome. Like the gradual vision loss experienced by BBS patients, worms infected with BBS gradually lost the ability to sense light as they age.

Through a series of several other experiments, the team discovered that the BBSome plays a role in light sense regardless of its role in cilia. In one scenario, they mutated C. elegans to remove all cilia; In a second experiment, they left the cilia on the worms but BBS prevented some from reaching the cilia. In both cases, the worms were still able to sense light, as long as some BBS was operating in the rest of the cell.

“It’s a fantastic display of the power of model organisms,” said Xinxing Zhang, a postdoctoral researcher in Xu’s lab and lead author of the study. “Cilia are essential to most organisms. But we can remove cilia from C. elegans and still be alive, allowing us to explore this unexpected role of some BBS completely independently of cilia.”

Xu’s lab previously discovered that C. elegans senses light through a receptor protein called LITE-1 that is located on the surface of neurons and sends signals to the central nervous system to respond to light (in the case of worms, by moving away from it).

In this latest study, the team found that when BBS malfunctions inside the cell, LITE-1 receptors are pulled back into the cell from the surface and then dissociated, preventing the worms from sensing light.

In a second genetic screen, the scientists discovered that the degradation process of LITE-1 is controlled by another protein called DLK. BBSome prevents DLK from initiating a chain reaction that inappropriately breaks down LITE-1.

Both the BBSome and DLK are conserved in humans, and the researchers were able to show that the BBSome similarly inhibits DLK expression in human cells. They believe that the BBS Some – DLK – photosynthetic pathway could be involved in the vision loss that is so prominent in patients with Bardet-Biedl syndrome.

“Since BBS is known to result from defects in the BBSome, there has been a long-standing assumption that the disorder must be related to the cilia,” said Xu, who is also a professor of molecular and integrative physiology at UM College of Medicine. “We do not question that BBS is related to defects in the cilia. We are only providing direct evidence that BBS can also act outside the cilia, and has a role related to light sensation for the development of BBS treatments.”

Structural insights into cilia assembly

more information:
Cilia-independent function of BBS is some mediated by DLK-MAPK signaling in C. developmental cell (2022). DOI: 10.1016/j.devcel.2022.05.005.… 1534-5807 (22) 00333-1

Presented by the University of Michigan

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2022-05-31 15:00:02

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