Most cases of amyotrophic lateral sclerosis (ALS) are sporadic, meaning that there is no family history of the disease. A small percentage, estimated to be five percent or slightly more, have familial ALS with a known genetic cause, the most common of which involves a noncoding sequence associated with the C9orf72 gene. A six-nucleotide sequence—GGGGCC—is usually repeated approximately 15 times, but in the disease state the sequence is expanded to hundreds or even thousands of repeats. These expansions have also been associated with other neurodegenerative diseases, including frontotemporal lobar degeneration (FTD), Alzheimer’s disease, Parkinson’s disease, Lewy body dementia and more.
The repeats yield two products thought to play roles in neurodegeneration. Repeat containing RNA foci accumulate in tissues and may alter RNA metabolism. Also, dipeptide repeats (DPRs) are translated from some of the RNAs produced, yielding peptides composed of two amino acids that are also found to aggregate in patient tissues. The exact roles that RNA foci and DPRs play in neurodegeneration is still under investigation.
A research team led by Robert Baloh of Cedars-Sinai Medical Center in Los Angeles and Senior Research Scientist Cathleen Lutz of JAX developed a mouse model to investigate repeat expansion in the C9orf72 gene, publishing the results online in Neuron on December 2. The mice express a repeat isolated from a human C9orf72 patient in the context of normal genetic regulation, and they developed RNA foci and produced DPRs at levels similar to those seen in patient tissues. Interestingly, however, the mice did not develop neurodegeneration during their normal lifespans, indicating that other factors, such as environmental stress or additional genetic factors, may be needed to develop the disease phenotype in humans, even with the presence of RNA foci and DPRs. Another group that developed mice with artificial overexpression of the repeat did find neurodegeneration, but it’s possible that the overexpression drove other toxicities unrelated to human disease progress.
Although they do not develop neurodegeneration, the mice are extremely valuable for studying the pre-symptomatic phase of the disease and to investigate what other stresses or insults may be necessary to progress to degeneration. The investigators also showed that anti-sense oligonucleotides that bound to the C9orf72 transcript reduced RNA foci and DPRs in cultured cells. The mice are therefore a key player in developing new therapeutic strategies that reduce the intracellular burden of the repeat and potentially delay or prevent disease.