Cerebral cavernous malformations (CCM) is a rare disease that causes anomalies in tiny capillaries that transport blood throughout the brain. The disease manifests as irregularities that resemble raspberries, most often in the brain, that can lead to hemorrhage, stroke and seizures in afflicted individuals. The disease involves defects in one of three CCM genes (CCM1, CCM2, or CCM3) and affects nearly one in six thousand people. Currently, there is no clinically approved therapy to treat this disease; patients rely on invasive brain surgery for treatment, but some extreme forms cannot be treated surgically.
One of the main hurdles in CCM research has been identifying cell signalling pathways that can be targeted to treat patients. A team at The Hospital for Sick Children (SickKids), led by Dr. Brent Derry, Senior Scientist in the Developmental & Stem Cell Biology Program at SickKids is tackling this challenge.This research was published on April 17 in Nature Communications.
By screening every gene in the genome, the team identified a cell signalling network called the ERK5 pathway that is overactivated in the absence of CCM1. While this discovery had been made a few years ago in vertebrate models such as zebrafish and mice, this was the first time that the function of CCM1 in C. elegans was proven to be conserved. This exciting discovery validates the use of this small worm to screen for molecules that are regulated by the ERK5 pathway.
This small nematode worm, C. elegans, has proven to be very useful. While C. elegans do not have blood vessels, these animals are very similar to humans at the cellular level. Genetic similarities between the worms and humans mean that discoveries made in the worm may be applicable to humans. Learn more about the use of nematode worms in research.
Since this organism has all three CCM genes, there is the potential to systematically inhibit the function of any of these three genes and use powerful screening techniques to return cells back to normal. This is precisely the approach taken by the research team.
To determine how overactivation of the ERK5 pathway leads to CCM-like cellular defects, the team identified every gene that is altered when the ERK5 is overactivated and found that the zinc transporter zipt-2.3 was expressed at much lower levels. Since these zinc transporters are important to properly store zinc, the team examined whether zinc localization is disturbed within cells. The absence of zipt-2.3 resulted in the failure of cells to keep zinc locked away in storage vessels. Failure to properly store zinc in the cell leads to redistribution throughout the body. This, Derry says, might be the reason why defects occur in the cells of the vasculature of patients with CCM.
“We used a completely unbiased approach to understand how the CCM1 gene functions in a tiny worm,” says Derry. “The unexpected discovery that it regulates zinc storage to control cell survival opens exciting new questions that might help us devise new treatments for patients.”
The research done on the worms was then validated in zebrafish and CCM patient samples with an international team of collaborators.
Last year the team published a drug screen for CCM active compounds that revealed new components of the CCM regulatory network and foreshadowed some of the proteins in the CCM1 pathway identified in this study by former graduate student Dr. Eric Chapman.
As the search for therapies to treat CCM disease remains an intense focus in the research community, Derry and his team have proven that C. elegans will be a critical tool for identifying molecules that might allow for the treatment to manage progression of this currently incurable disease. “I feel very confident that we can learn a lot about this disease from the humble worm,” says Derry.
This research was funded by the Canadian Institutes of Health Research and SickKids Foundation. This study is an example of how SickKids is making Ontario healthier, wealthier and smarter (www.healthierwealthiersmarter.com).
Source of text and image: SickKids Hospital:
Original research article in Nature Communications:
Chapman EM, Lant B, Ohashi Y, Yu B, Schertzberg M, Go C, Dogra D, Koskimäki J, Girard R, Li Y, Fraser AG, Awad IA, Abdelilah-Seyfried S, Gingras AC, Derry WB. A
conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis. Nat Commun. 2019 Apr 17;10(1):1791. doi: 10.1038/s41467-019-09829-z.