Research funded by The ALS Association using Ice Bucket Challenge donations recently led to a significant discovery in understanding a disease pathway behind the most frequent cause of inherited ALS and frontotemporal dementia (FTD).

Top ALS researchers published three high-impact papers in Nature Communications, delving into the underlying mechanism of how the C9orf72 gene expansion is translated into toxic proteins. Information uncovered in these papers inform therapeutic development of drugs targeting the C9 expansion, which have the potential to make an impact on the largest population of people living with familial, or inherited, ALS.

The C9orf72 gene expansion is often expanded from 25 repeats up to thousands of repeats. This gene expansion is then made into toxic proteins called dipeptide repeat proteins (DPRs) through a unique type of translation called repeat-associated non-AUG (RAN) translation.

These toxic DPRs classically accumulate in protein aggregates, or clumps of proteins, in motor neurons, the cells that die during ALS disease. Numerous studies have been published citing several ways that DPRs are toxic to cells. However, researchers’ understanding of RAN translation is lacking in the scientific community.

Dr. Peter Todd at University of Michigan, Dr. Don Cleveland and Dr. Shuying Sun at University of California and Johns Hopkins University, respectively, and Dr. Clotilde Lagier-Tourenne at Massachusetts General Hospital -- all supported by The ALS Association -- uncovered the underlying pathways of RAN translation in the papers published in Nature Communications.

Each paper demonstrated some commonalities and differences behind the mechanism of RAN translation, advancing the scientific communities’ understanding of how the C9 gene expansion is translated and warranting further study. Importantly, they agreed on the finding that cellular stress is a common and critical factor needed to initiate RAN translation. These stress conditions could create a potential feed-forward loop that contributes to neurodegeneration.

Also, they found that phosphorylation of a major translation initiation factor, called eIF2α, also was a significant contributor to RAN translation initiation. Whether a 5’ cap was needed for RAN translation initiation is still under debate. The researchers also found that inhibiting specific factors involved in RAN translation could inhibit this process. These factors could serve as potential ALS therapeutic targets to inhibit RAN translation in people living with C9orf72 ALS and FTD.

“Mutations C9orf72 impacts one in 10 people living with ALS,” said Dr. Lucie Bruijn, chief scientist for The ALS Association. “Identifying therapeutic approaches for this target will have significant impact. These papers from The ALS Association-funded scientists are critical to moving the development of therapeutics forward and enhancing our understanding of the disease process.”

For more detailed information, please visit The ALS Association-sponsored ALS Research Consortium article: Stressed-Out Cells Translate C9orf72 Repeats, Unleash Toxic Peptides.

To see how ALS Ice Bucket Challenge donations are being put to work, click here.

Paper Citations

Tabet R, Schaeffer L, Freyermuth F, Jambeau M, Workman M, Lee CZ, Lin CC, Jiang J, Jansen-West K, Abou-Hamdan H, Désaubry L, Gendron T, Petrucelli L, Martin F, Lagier-Tourenne C. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts. Nat Commun. 2018 Jan 11;9(1):152.  PubMed LINK

Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ, Goldstrohm AC, Barmada SJ, Todd PK. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat Commun. 2017 Dec 8;8(1):2005. PubMed LINK

Cheng W, Wang S, Mestre AA, Fu C, Makarem A, Xian F, Hayes LR, Lopez-Gonzalez R, Drenner K, Jiang J, Cleveland DW, Sun S. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat Commun. 2018 Jan 4;9(1):51. PubMed LINK