Scientists have discovered a new role for protein complexes at the heart of Bardet-Biedle syndrome

Scientists have identified a new role for a protein complex at the heart of a human hereditary disease called Bardet-Biedle Syndrome (BBS), but there is currently no cure.

Bardet-Biedle syndrome occurs when the BBSome protein complex becomes dysfunctional. BBS is classified as a ciliary disease because it regulates the morphology and function of cilia and the hair-like structure of the cell surface.

However, a wide range of symptoms associated with BBS (most commonly vision loss, obesity, extra fingers and toes, kidney dysfunction) have hypothesized that the cause of the syndrome is not solely within the cilia. I am.

In a new study published in Developmental Cell, a team at the University of Michigan Institute for Life Sciences provides the first known direct evidence of these hypotheses. Their findings show that BBSome is at least one common model species that functions outside the cilia to support vision.

The discovery was made by a scientist in the laboratory of Shawn Xu, an LSI faculty member, investigating how small roundworms called Caenorhabditis elegans can sense light in the absence of eye-like organs. It started when. Because C. elegans has a simple, well-mapped nervous system, Xu Labs use them as models to understand the basic biology behind different forms of sensation.

The team performed a genetic screen. This is the process of introducing random mutations to identify the genes required for a particular biological process and to find the genes involved in the worm’s ability to respond to light. Most of the mutations that caused the worm to stop sensing light were found to be in BBSome. And, like the progressive loss of vision experienced by BBS patients, worms with the BBSome mutation gradually lost their ability to sense light with age.

Through a series of further experiments, the team discovered that BB Some plays a role in the sense of light independently of its role in cilia. In one scenario, C. Mutated elegans to remove all cilia. In the second experiment, they left the cilia on the worm, but prevented the BB Some from reaching the cilia. In both cases, the worm was able to detect light as long as the BB Same was working on the rest of the cell.

It’s a great demonstration of the power of model organisms. Cilia are essential for most organisms. But C. Although it is possible to remove cilia from elegans, it can still survive and reveal this unexpected role of BB Some, which is completely independent of cilia. “

Xinxing Zhang, a postdoctoral fellow at Xu Labs and the lead author of the study

Xu’s laboratory is C. We have previously discovered that elegans sense light through a receptor protein called LITE-1 on the surface of neurons and send signals to the central nervous system to respond to light (in the case of worms, there). By moving away from)).

In this latest study, the team says that when BBSome becomes intracellularly dysfunctional, the LITE-1 receptor is pulled back from the surface into the cell and then degraded, preventing the worm from sensing light. I found.

In a second genetic screen, scientists discovered that the process of degrading LITE-1 is regulated by another protein called DLK. BBSome prevents DLK from initiating a chain reaction that improperly degrades LITE-1.

Both BBSome and DLK are conserved in humans, and researchers have been able to show that BBSome also blocks DLK expression in human cells. They believe that this BBSome-DLK-photosensor pathway may be involved in vision loss, which is very prominent in patients with Bardet-Biedle syndrome.

“Because BBS is known to be caused by defects in BBSome, there has been a long-standing assumption that this disorder must be related to cilia,” said Xu, a professor of molecular and integrated physiology at UMM Medical School. Mr. says. “We do not dispute that BBS is associated with ciliary defects. We only provide direct evidence that BBSome can function outside of cilia, where Plays a role related to the sense of light. Perhaps this can broaden the horizons of how to develop treatments for BBS. “

This study was supported by the National Institute of Health.