Summary: Researchers report that a repeated DNA sequence in the C9orf72 gene produces toxic protein when cells are exposed to starvation, environmental toxins, viral infection or other stresses.
Source: University of Michigan
University of Michigan-led team advances understanding of how stress-driven translation of repeat sequences may contribute to neurodegenerative diseases such as ALS and frontotemporal dementia
In a study published in Nature Communications, investigators describe a stress-responsive process that amplifies production of toxic proteins from a repeat expansion in the C9orf72 gene, a mutation linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The work reveals how cellular stress—triggered by viral infection, nutrient deprivation, toxins or accumulation of misfolded proteins—can activate an atypical form of protein synthesis called repeat-associated non-AUG (RAN) translation, creating a self-reinforcing cycle that promotes further stress and toxic-protein production.
RAN translation enables protein synthesis to begin at repeat expansions without a conventional AUG start codon and has been implicated in several repeat-expansion disorders, including Huntington’s disease, various ataxias and myotonic dystrophy. The new study shows that, for the G4C2 repeats in C9orf72, RAN translation initiates via a mechanism that depends on the mRNA cap structure and the eIF4A helicase and uses a CUG start codon. Crucially, the authors demonstrate that activation of the cell’s integrated stress response (ISR) selectively enhances RAN translation from both G4C2 repeats in C9orf72 and CGG repeats that cause fragile X–associated tremor/ataxia syndrome (FXTAS).
According to first author Katelyn Green, a University of Michigan graduate student in cell and molecular biology, “Under normal conditions many stressed cells reduce overall protein production, but in this case cellular stress actually boosts synthesis of RAN-derived toxic proteins, establishing a loop that could drive degeneration of neurons.” Senior author Peter Todd, M.D., associate professor of neurology at U-M, adds that the findings suggest environmental or physiological stressors might influence when and how people with repeat-expansion mutations begin to develop neurodegenerative disease symptoms.
The team found that ISR activation enhances RAN translation through a mechanism that depends on phosphorylation of the translation initiation factor eIF2α, which alters start-codon selection fidelity. At the same time, both the CGG and G4C2 repeat RNAs promote formation of stress granules and cause broad suppression of normal translation in a phosphorylated-eIF2α–dependent manner. Together, these effects create conditions that favor continued production of aberrant, RAN-derived proteins and amplify cellular stress—a feed-forward loop that may contribute to neurodegeneration.
Importantly, the same stress-amplifying pattern was observed at the CGG repeat associated with FXTAS, indicating that this ISR-driven enhancement of RAN translation could represent a shared molecular mechanism across multiple repeat-expansion disorders. By clarifying how stress pathways intersect with unconventional translation from repeat sequences, the study points toward potential therapeutic strategies that interrupt this vicious cycle to reduce toxic protein accumulation.
Authors: Katelyn M. Green, M. Rebecca Glineburg, Michael G. Kearse, Brittany N. Flores, Alexander E. Linsalata, Stephen J. Fedak, Aaron C. Goldstrohm, Sami J. Barmada & Peter K. Todd. Affiliations include the University of Michigan, with additional contribution from the University of Pennsylvania and the University of Minnesota.
Funding: Supported by VA Research Biomedical Laboratory Research and Development, the National Institutes of Health, the David and Lucile Packard Foundation, the Michigan Alzheimer’s Disease Center and Protein Folding Disease Initiative, and Ann Arbor Active Against ALS.
Source and Publisher: Report prepared by Haley Otman for the University of Michigan and organized by NeuroscienceNews.com.
Original Research: Full open-access article titled “RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response,” published in Nature Communications (published online December 8, 2017). The research analyzes how RAN translation at G4C2 and CGG repeats is regulated by the integrated stress response and details the molecular requirements for initiation and ISR dependence.
MLA: University of Michigan. “Genetic Mutations Cause ‘Vicious Cycle’ in Most Common Form of ALS.” NeuroscienceNews. 8 December 2017.
APA: University of Michigan (2017, December 8). Genetic Mutations Cause ‘Vicious Cycle’ in Most Common Form of ALS. NeuroscienceNews.
Chicago: University of Michigan. “Genetic Mutations Cause ‘Vicious Cycle’ in Most Common Form of ALS.” NeuroscienceNews. December 8, 2017.
Abstract (summary)
Repeat-associated non-AUG (RAN) translation permits protein synthesis initiation at disease-causing repeat expansions through unconventional mechanisms. Because RAN translation contributes to pathology in several neurodegenerative disorders, defining its regulation is important for therapeutic development. This study dissects C9RAN translation at G4C2 repeats that underlie C9orf72-associated ALS and FTD and compares it with CGG RAN translation linked to FXTAS. The authors show that C9RAN initiation depends on the mRNA cap and the eIF4A helicase and uses a CUG start codon. Both C9RAN and CGG RAN translation are selectively enhanced by activation of the integrated stress response. Enhancement requires phosphorylation of eIF2α, which alters start codon fidelity. Concurrently, both repeat types promote phosphorylated–eIF2α–dependent stress granule formation and global translation suppression. These observations support a model in which repeat expansions induce cellular stress states that favor RAN translation of toxic proteins, creating a feed-forward loop that may drive neurodegeneration.