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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Intronic GGGGCC repeat expansions in C9orf72 are a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• These expansions drive repeat-associated non-AUG (RAN) translation, producing toxic proteins that lead to neurodegeneration.
• The regulation of RAN translation, particularly its dependence on mRNA cap structures, varies across cell types.

Purpose of the Study:

• To investigate the cell-type-specific mechanisms of RAN translation in neurons.
• To explore the role of the 5' 7-methylguanosine mRNA cap in RAN translation efficiency.
• To identify factors contributing to neuronal vulnerability in nucleotide repeat expansion disorders.

Main Methods:

• Utilized rodent neurons and human iNeurons to study RAN translation from CGG and GGGGCC repeats.
• Employed an eIF4E inhibitor to assess the impact of cap-dependent translation inhibition.
• Investigated start codon stringency and the roles of eukaryotic initiation factors eIF1 and eIF5.

Main Results:

• Neurons favor cap-independent RAN translation, independent of the mRNA cap structure.
• Inhibiting cap-dependent translation enhances RAN translation specifically in neurons.
• Neurons exhibit increased start codon stringency, favoring cap-independent RAN translation, linked to eIF1 redistribution and modulated by eIF5.

Conclusions:

• Neuronal translational machinery possesses unique features that promote cap-independent RAN translation.
• These findings highlight neuron-specific translational regulation as a key factor in C9orf72-related neurodegenerative diseases.
• Understanding these mechanisms may reveal novel therapeutic strategies for ALS and FTD.