Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs.
Publication Year:
2022
PubMed ID:
36585921
Funding Grants:
Public Summary:
Circular RNAs are special, stable molecules made by cells, and their exact role isn’t fully understood yet. Because they last a long time in the body, they can be useful markers for diseases.
This study looked at circular RNAs in people with ALS, a disease that affects muscles and nerves. The researchers found that certain circular RNAs were higher or lower in the muscles of ALS patients compared to healthy people, even when the related normal RNAs didn’t change much.
They also saw similar changes in nerve cells grown in the lab from patients with ALS-related mutations, and in muscle tissue from mice with an ALS-like disease. Interestingly, some circular RNAs that were increased in ALS muscles were decreased in spinal cord tissue from the same patients and mice.
Scientific Abstract:
Circular RNAs are abundant, covalently closed transcripts that arise in cells through back-splicing and display distinct expression patterns across cells and developmental stages. While their functions are largely unknown, their intrinsic stability has made them valuable biomarkers in many diseases. Here, we set out to examine circRNA patterns in amyotrophic lateral sclerosis (ALS). By RNA-sequencing analysis, we first identified circRNAs and linear RNAs that were differentially abundant in skeletal muscle biopsies from ALS compared to normal individuals. By RT-qPCR analysis, we confirmed that 8 circRNAs were significantly elevated and 10 were significantly reduced in ALS, while the linear mRNA counterparts, arising from shared precursor RNAs, generally did not change. Several of these circRNAs were also differentially abundant in motor neurons derived from human induced pluripotent stem cells (iPSCs) bearing ALS mutations, and across different disease stages in skeletal muscle from a mouse model of ALS (SOD1(G93A)). Interestingly, a subset of the circRNAs significantly elevated in ALS muscle biopsies were significantly reduced in the spinal cord samples from ALS patients and ALS (SOD1(G93A)) mice. In sum, we have identified differentially abundant circRNAs in ALS-relevant tissues (muscle and spinal cord) that could inform about neuromuscular molecular programs in ALS and guide the development of therapies.