Emery-Dreifuss muscular dystrophy (EDMD) is a devastating genetic disease that causes progressive muscle weakness and wasting. EDMD is caused by mutations in proteins within the nuclear envelope, yet the disease disrupts the organization and function of entire muscle cells. A new study by UC Davis researchers reveals one mechanism that may explain this connection.

By tracking the movement of fluorescent nanoparticles inside worms with EDMD-associated genetic mutations, the researchers discovered that cells carrying these mutations contain far fewer ribosomes than usual. Without enough ribosomes, the interior of the cell becomes unusually sparse, which alters how molecules move and ultimately disrupts the cell’s organization.

The team showed that they could ramp up ribosome production in the mutant worms by genetically activating the mTOR pathway, a regulator of cell growth, pointing to a potential avenue for developing therapies to treat EDMD in people. Their findings are published in Science Advances.

“Our results suggest that ribosome depletion plays a key role in EDMD pathogenesis,” said first author Xiangyi Ding, a recent Ph.D. graduate in the Integrative Genetics and Genomics graduate group. “This is exciting, because therapeutic strategies could target multiple points in this pathway.”

Using Worms to Understand Human Diseases

EDMD is caused by genetic mutations in the genes that encode proteins (lamins and emerin) that support the nuclear envelope, the double membrane that surrounds a cell’s genetic material. Previous research has focused on how EDMD-associated mutations disrupt the mechanical stability of the nucleus and the regulation of gene expression, but EDMD changes the overall architecture of muscle cells, not just their nuclei.

“We wanted to know how these nuclear envelope proteins are able to cause cell-wide disorganization,” said Ding.

To investigate this, the team introduced EDMD-associated genetic mutations into the millimeter-long roundworm Caenorhabditis elegans. Lamins and emerin are conserved across animals, and worms carry counterparts of the proteins that are mutated in EDMD, studying these proteins in worms provides a relatively fast way to pinpoint what goes wrong.

“These worms had swimming defects, and their severity matched what is seen in the clinic—mutations that cause more severe disease in humans also caused more severe defects in the worms,” said Daniel Starr, a professor of molecular and cellular biology, who co-led the study with G.W. Gant Luxton, an adjunct professor of molecular and cellular biology. 

“This means that we can use C. elegans as a model to understand the clinical variants of EDMD,” said Luxton. “With worms, we can do so much more, so much faster.”

To see what was happening inside the worms’ cells, the researchers engineered the worms to produce tiny fluorescent particles called GEMs (genetically-encoded multimeric nanoparticles) and then used time-lapse videos to track the GEMs’ movements. 

In normal worm cells, GEMs move slowly because their motion is restricted by the high abundance of ribosomes that crowd the cytoplasm like packing peanuts. In contrast, the researchers showed that the GEMs could zip about much faster and more freely in worms with EDMD-associated mutations because there were fewer ribosomes to buffer their movements. 

Replenishing Ribosomes — a Potential Treatment?

The team traced this lack of ribosomes back to the nucleolus—a structure nestled within the nucleus where ribosomes are built. They showed that worms with EDMD-associated mutations had smaller nucleoli and made fewer ribosomes. 

“By controlling the nucleolus, the lamin mutation can affect the entire cell's organization,” said Ding.

However, they found that they could partially override this effect in the EDMD worms by genetically removing a brake on the mTOR pathway, which stimulated their nucleoli to produce more ribosomes.

“The mTOR pathway is central to metabolism and regulating the number of ribosomes,” said Starr. “This suggests that it could be a potential avenue for treatment.”

Beyond EDMD, the researchers say that their approach could provide insights into a range of other conditions, including aging, neurodegenerative diseases, and other “laminopathies” (diseases caused by lamin mutations). 

“There are hundreds of different mutations in this lamin gene that are associated with a variety of diseases,” said Luxton. “We’re just scratching the surface with this paper.”

Additional authors on the study are Sweta Kumari and Ellen Gregory, UC Davis. 

The work was funded by the National Institutes of Health and by an Allen Distinguished Investigator Award, a Paul G. Allen Frontiers Group advised grant of the Paul G. Allen Family Foundation. This research utilized advanced scientific facilities at UC Davis, including the Light Microscopy Core.