Researchers have gained insight into how a toxic protein, known to trigger muscular dystrophy, could be ‘switched off’ – a pre-clinical discovery that could spearhead a treatment for the debilitating disease which affects around 870,000 people worldwide, including more than 1,000 Australians.
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive, muscle-weakening, and currently untreatable condition characterised by the death of muscle cells and tissue, and critically, people with FSHD have reduced levels of the ‘silencing’ gene SMCHD1.
Using pre-clinical models of the disease the international collaboration, led by Walter and Eliza Hall Institute (WEHI), found boosting SMCHD1 function could silence the production of a toxic protein known to trigger the deterioration of healthy muscles.
SMCHD1 was discovered by WEHI researchers in 2008, which at the time was flagged as breakthrough for FSHD, and WEHI’s Professor Marnie Blewitt explained that the current research “rewrites our understanding of how SMCHD1 switches off the toxic protein, clarifying how the gene’s ‘silencing’ capabilities could be boosted to find a future treatment for the condition.”
“While most people with FSHD have a normal life expectancy, their quality of life is significantly decreased due to the challenges they experience because of the serious muscle weakness brought on by this disease. We want to improve their health and quality of life,” she said.
Professor Blewitt, the Acting Deputy Director and Laboratory Head at WEHI, leads the only drug discovery effort in the world that leverages in-depth understanding of SMCHD1 to design novel therapies to treat degenerative disorders like FSHD.
She said it was invaluable to know the gene could be safely boosted in the lab with no adverse side-effects, after years of research flagging the possibility.
“The less SMCHD1 people have, the worse the disease symptoms, as SMCHD1 normally silences the expression of the protein known to destroy muscle function in FSHD,” Professor Blewitt explained.
“When this process malfunctions, it causes this toxic protein to be produced in excess, impacting healthy muscles, which 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.”
“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.”
SMCHD1 is a member of the structural maintenance of chromosomes (SMC) family, and SMC proteins are ATPases highly conserved among the three phyla of life. They were first discovered in 1993 and are essential for successful chromosome transmission during the replication and segregation of the genome in all organisms.
SMC proteins also interact with other proteins in a range of other chromosomal transactions, including chromosome condensation, sister-chromatid cohesion, recombination, DNA repair and epigenetic silencing of gene expression.
The importance of correct epigenetic regulation to normal development and differentiation has long been known and modern genomic techniques have revealed sophisticated mechanisms behind epigenetic control, where DNA methylation, post-translational histone modifications, and chromatin conformation come together in a dynamic fashion to regulate gene expression. However, the complex interplay between different modes of epigenetic control, often between those considered to have opposing functions (like bivalent chromatin), has precluded straightforward interpretations.
One approach to understanding such a complex biological problem is to unravel the factors involved in the process using unbiased genetic screen screening approaches, which have identified novel epigenetic regulators in yeast, plants, flies, and mammals.
In 2018, WEHI researchers discovered that SMCHD1 gathers the genes that it normally silences into specific regions of the nucleus in each cell, and Andres Tapia del Fierro, a PhD student in Prof Blewitt’s lab, said his findings showed the gene’s gathering ability was not connected to its silencing functionalities.
“This was an unexpected yet crucial finding, that really took the team by surprise,” Dr del Fierro said.
“Without this fundamental discovery we would still think these two functions are linked, seeing 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.”
WEHI researchers are instead focusing on other activities of SMCHD1 that could potentially be boosted to enhance its gene-silencing abilities and are currently screening thousands of drug-like molecules in search of chemicals that could boost SMCHD1 activity.
“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,” Dr del Fierro said.
“In order to create therapeutics against SMCHD1, we need to have an in-depth understanding into how the protein works: while we do not yet know how to boost SMCHD1 function in a human context, knowing what will not work allows us to start a process of elimination that will bring us closer to hitting the molecular jackpot.
“Every finding also allows us to gain a deeper understanding of the complex SMCHD1 protein – and that is the beauty of scientific discovery.”