Research Paper Volume 14, Issue 24 pp 9832—9859
Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs
- 1 Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
- 2 Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- 3 Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA
- 4 Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- 5 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- 6 Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- 7 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- 8 Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- 9 Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
Received: October 29, 2022 Accepted: December 13, 2022 Published: December 30, 2022
https://doi.org/10.18632/aging.204450How to Cite
Copyright: © 2022 Tsitsipatis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 (SOD1G93A). 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 (SOD1G93A) 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.