Bardet-Biedl Syndrome or BBS is a rare genetic condition that affects primary cilia and impacts multiple body systems. The syndrome has highly variable symptoms which may include retinal degeneration, obesity, reduced kidney function, and polydactyly. Unfortunately, there is no cure for BBS. However, scientists from the University of Michigan (U-M) Life Sciences Institute (LSI) report they have identified a new role for a protein complex at the center of BBS. Their findings offer new insights into the rare genetic disease.
Results from their study are published in the journal Developmental Cell in a paper titled, “A cilia-independent function of BBSome mediated by DLK-MAPK signaling in C. elegans photosensation.”
“BBS is a genetic disorder that affects primary cilia,” wrote the researchers. “BBSome, a protein complex composed of eight BBS proteins, regulates the structure and function of cilia, and its malfunction causes BBS in humans. Here, we report a cilia-independent function of BBSome. To identify genes that regulate the C. elegans photoreceptor protein LITE-1 in ciliated ASH photosensory neurons, we performed a genetic screen and isolated bbs mutants. Functional analysis revealed that BBSome regulates LITE-1 protein stability independently of cilia.”
BBS arises when the BBSome protein complex malfunctions. However, the researchers at LSI sought to determine whether the cause of the syndrome may not just lie within the cilia.
Scientists in the lab of LSI faculty member Shawn Xu, PhD, investigated how Caenorhabditis elegans can sense light despite having no eye-like organs. The Xu lab used C. elegans as a model to understand the fundamental biology behind various forms of sensation.
The scientists performed a genetic screen to find the genes involved in the worms’ ability to respond to light. Most of the mutations that caused worms to stop sensing light turned out to be in the BBSome. The worms with BBSome mutations progressively lost the ability to sense light as they aged just as BBS patients experience vision loss.
Through further experiments, the team discovered that the BBSome plays a role in light sensation independent of its role in the cilia. In their first experiment, they mutated C. elegans to remove all cilia; in a second experiment, they left the cilia on the worms but prevented the BBSome from getting to the cilia. In both cases, the worms were still able to sense light, as long as BBSome functioned in the rest of the cell.
“It’s a great demonstration of the power of model organisms,” explained Xinxing Zhang, PhD, a postdoctoral researcher in the Xu lab and the study’s lead author. “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.”
Xu’s lab previously discovered that C. elegans sense light through a receptor protein called LITE-1 that sits at the surface of neurons and sends signals to the central nervous system to respond to the light.
In this current study, the team found that when BBSome malfunctions within the cell, LITE-1 receptors are pulled back into the cell from the surface and then broken down, preventing the worms from sensing light.
In a second genetic screen, the team observed that the process of degrading LITE-1 is controlled through another protein called DLK. The BBSome prevents DLK from starting a chain reaction that inappropriately breaks down LITE-1.
Both BBSome and DLK are conserved in humans, and the researchers were able to show that BBSome similarly blocks DLK expression in human cells.
The scientists believe that this BBSome–DLK–photosensor pathway could be involved in the vision loss that is so prominent in patients with BBS.
“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,” said Xu, who is also a professor of molecular and integrative physiology in the U-M 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.”
The findings provide novel insights into the rare genetic disease and may pave the way for future therapies.