Switching off the protein that triggers muscular dystrophy

A global research team led by the Walter and Eliza Hall Institute of Medical Research (WEHI) has gained insight into how a toxic protein, known to trigger muscular dystrophy, could be ‘switched off’ — a preclinical discovery that could spearhead a treatment for this debilitating disease.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive, muscle-weakening condition characterised by the death of muscle cells and tissue. SMCHD1, a gene discovered by WEHI researchers in 2008, is critical for switching off the production of the protein that causes this incurable and untreatable disease.

“The less SMCHD1 people have, the worse the disease symptoms,” explained Professor Marnie Blewitt, Acting Deputy Director and Laboratory Head at WEHI.

“That’s because SMCHD1 normally silences the expression of the protein known to destroy muscle function in FSHD. When this process malfunctions, it causes this toxic protein to be produced in excess, impacting healthy muscles.

“This is why our team has dedicated years to finding ways to boost SMCHD1 function, in hopes of restricting the production of this toxic protein and protecting muscle function.”

Working with Leiden University Medical Center, the researchers found that boosting SMCHD1 function limited the production of the toxic protein in preclinical models of the disease, with no adverse side effects. Their research, published in the journal Nature Communications, also rewrites a previous discovery made about how SMCHD1 executes its silencing capabilities.

In 2018, WEHI researchers revealed SMCHD1 gathers together genes that it normally silences into specific regions of the nucleus in each cell. PhD student Andres Tapia del Fierro, the new paper’s first author, said his findings showed the gene’s gathering ability is not actually connected to its silencing functionalities.

“This was an unexpected yet crucial finding that really took the team by surprise,” Tapia del Fierro said.

“Without this fundamental discovery, we would still think these two functions are linked.

“This would have seen us dedicate years towards trying to find new ways to boost SMCHD1 function, by boosting its ability to gather genes — which we now know won’t work.”

The researchers are instead focusing on other activities of SMCHD1 that could potentially be boosted to enhance its gene-silencing abilities. Tapia del Fierro said, “Some of the most significant scientific discoveries have come from these types of mechanistic findings that transform our understanding and allow us to break apart a protein’s different activities to analyse its various roles.

“While we don’t yet know how to boost SMCHD1 function in a human context, knowing what won’t work allows us to start a process of elimination that will bring us closer to hitting the molecular jackpot.”

The WEHI researchers are currently screening thousands of drug-like molecules in search of chemicals that can boost SMCHD1 activity. Promising molecules will then be refined to develop drugs to treat FSHD, or even prevent the disease in people carrying FSHD mutations.

“The next step is to figure out how to translate these milestone findings to benefit humans by determining the best way to boost SMCHD1 and its silencing powers to hopefully find a cure for FSHD,” Blewitt said.

Image caption: SMCHD1 is involved in gathering pieces of DNA together. In the image two of these pieces are marked with magenta and green dots, while all the DNA is marked in turquoise. Image credit: WEHI.