Researchers at the Keck School of Medicine of USC have made a significant advance toward understanding and potentially treating a rare cardiomyopathy (heart muscle disease) present from birth. The condition, known as AARS2-associated cardiomyopathy, is caused by an inherited mutation in the alanyl-transfer RNA (tRNA) synthetase 2 (AARS2) gene and is often fatal within the first year of life. Currently, no cure or treatment exists.
Previous efforts to treat AARS2-related cardiomyopathy have focused on repairing mutations in the AARS2 gene. But a new study suggests that another gene, PCBP1, may offer an alternative way to intervene.
Although PCBP1 is not the gene that causes the disease, researchers found that it helps control how the non-mutated AARS2 gene functions in heart cells, making it a new potential point of intervention to prevent heart damage. In mice and human heart cells grown in the lab, they found that silencing PCBP1 reproduced key features of the disease. They also discovered how the damage occurs, including disrupting mitochondria, which produce the energy that fuels cells.
The findings suggest that targeting PCBP1 may help restore healthy AARS2 function in heart cells. The research was partially funded by the National Institutes of Health and was recently published in the journal Nature Cardiovascular Research.
This is the first time that PCBP1 has been linked to this disease. “We were able to trace its effects on AARS2 down to the molecular level, which gives us strong evidence that PCBP1 can influence the development of this disease.”
Yao Wei Lu, PhD, study lead and corresponding author, assistant professor of medicine and member of the Hastings Center for Pulmonary Research at the Keck School of Medicine
In addition to potentially opening new avenues for treating AARS2-related cardiomyopathy, the findings may have broader relevance. Many other rare diseases that affect the heart, brain, and other organs also involve problems with mitochondria. By showing how these breakdowns occur at the genetic and cellular level, the study could point to new treatment strategies for a variety of disorders.
Linking AARS2 and PCBP1
PCBP1, short for poly(rC)-binding protein 1, codes for the protein of the same name. Working properly, this protein helps process genetic messages that tell cells how to work. When PCBP1 is missing, that process can go haywire.
In mice, Lu and his colleagues used a genetic approach that allowed them to remove PCBP1, but only in heart muscle cells. This helped them isolate the role of genes in heart development and disease.
The researchers then identified a series of events associated with PCBP1, AARS2, and heart muscle disease. When PCBP1 is missing, the genetic message from AARS2 is processed incorrectly, leading to AARS2-associated cardiomyopathy seen in human patients. The result is that mitochondrial activity is disrupted, reducing the cell’s energy supply. In an attempt to compensate, heart cells switch on stress signals that cause further damage.
The researchers also used human induced pluripotent stem cells (iPSCs), reprogrammed adult cells, to create heart muscle cells in the laboratory. When they turned off PCBP1, they saw similar effects in mitochondria, suggesting that the same process occurs in human cells.
comprehensive treatment capability
In addition to revealing key details about the mechanisms behind AARS2-related cardiomyopathy, the study produced a mouse model of the condition that will make it easier to study. Lu and his team are now exploring potential treatments in both mice and iPSCs.
They are also investigating whether a similar approach could help treat other diseases where mitochondrial problems damage the heart, brain, lungs or kidneys.
“We think what we found in the heart can apply to many of these organs, because the root cause—mitochondrial dysfunction—is the same,” Lu said.
Lu’s collaborators include his former mentor Da-Zhi Wang, PhD, of the University of South Florida, and Hong Chen, PhD, of Boston Children’s Hospital and Harvard Medical School; George Porter, MD, PhD, from the University of Rochester Medical Center, a pediatric cardiologist who led the analysis of mitochondrial function; Frank Conlon, PhD, from the University of North Carolina at Chapel Hill, who led the proteomics analysis; and Jesse Huang, PhD, of the Keck School of Medicine of USC, who helped create the iPSC-based model.
