Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation

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ID: 328580
2026
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Abstract
Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global alteration in neuronal start codon stringency as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with cytoplasmic redistribution of eIF1 in neurons and is reversed with overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and preferentially enhances cap-dependent RAN translation. Together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis.
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openalex_W7212296970 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Clare M. Wieland, Shannon E. Wright, Sydney Willey, Ishita Purwar, Samantha J Grudzien, Amy Krans, Erinn L Laimon, Melissa Asher, Adrian M. Isaacs, Amanda L. Garner, Peter K. Todd
Journal Nucleic Acids Research
Year 2026
DOI
10.1093/nar/gkag880
URL
https://doi.org/10.1093/nar/gkag880
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