Although recent research points to toxins from blue-green algae as a cause of amyotrophic lateral sclerosis (ALS), new research from Johns Hopkins suggests that ALS may be caused by a genetic mutation that leads to the accumulation of erroneous RNA that cannot make enough of its coding protein. However, instead of the bad protein and RNA, the genetic material itself may be the root cause of the problem.
Dr. Jiou Wang, an assistant professor at the Johns Hopkins University School of Medicine, published his work investigating the mutation in Nature. The mutation occurs in the gene C9orf72 and has been linked to both ALS and frototemporal dementia (FTD). Patients with ALS or FTD often have hundreds of hexanucleotide repeat expansions in the gene C9orf72, whereas healthy people normally have up to 20 repeats.
Dr. Wang and his team took a closer look at the snarled six-base DNA repeats and the RNA that is transcribed from them. Intriguingly, the long strands of DNA and RNA were bunching together to form 3D structures known as G-quadruplexes. In a G-quadruplex, guanine bases link together and form stacks that stick together like shelves. The RNA was also forming hairpins and bulges in the repeats. The different conformations of DNA and RNA were interfering with the normal functions of the nucleic acids.
The team also found that broken pieces of RNA formed during failed transcription of C9orf72 and were bound to at least 288 different proteins. When bound to the broken RNA, the proteins could not function appropriately, and some where found in the wrong places in cells. For example, nucleolin, a protein involved in making ribosomes, was found scattered throughout the nucleus of patients with ALS rather than near the site of ribosome synthesis.
Although this work has intriguing implications, the authors have not written off the possibility that the protein coded by C9orf72 is involved in ALS. “It could be simultaneous–bad RNA accumulating, plus you’re losing some of the protein itself,” said Dr. Wang. Dr. Margaret Sutherland from the National Institute of Neurological Disorders and Stroke stated, “The findings described in Dr. Wang’s paper open up a new pathogenic mechanism for ALS and FTD by providing insight into the biology associated with the C9orf72 mutation and identifying a potential path forward for therapy development.” The National Institute of Neurological Disorders and Stroke funded the study, along with the Robert Packard Center for ALS Research at Johns Hopkins, the Muscular Dystrophy Association, Target ALS, the ALS Association, the National Institute on Aging, the National Cancer Institute, the Maryland Stem Cell Research Fund, the Judith and Jean Pape Adams Charitable Foundation and the Samuel I. Newhouse Foundation.