Related Experiment Video
Updated: Oct 2, 2025
10:37
Toeprinting Analysis of Translation Initiation Complex Formation on Mammalian mRNAs
Published on: May 10, 2018
12.7K
Non-canonical initiation factors modulate repeat-associated non-AUG translation
Katelyn M Green1,2, Shannon L Miller1,2, Indranil Malik1
1Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
Human Molecular Genetics
|February 27, 2022
Summary
Repeat-associated non-AUG (RAN) translation produces toxic peptides in neurodegenerative diseases. Alternative initiation factors, particularly DENR, drive RAN translation and may offer novel therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Repeat-associated non-AUG (RAN) translation generates toxic peptides implicated in neurodegenerative diseases.
- RAN translation persists despite cellular stress that inhibits global translation via eIF2 phosphorylation.
Purpose of the Study:
- To investigate the role of alternative translation initiation factors in RAN translation.
- To identify potential therapeutic targets for neurodegenerative diseases linked to RAN translation.
Main Methods:
- In vitro, cell-based, and Drosophila models were employed.
- The function of alternative ternary complex factors (eIF2A, eIF2D, DENR, MCTS1) in RAN translation was assessed.
- Knockdown of DENR was performed to evaluate its effect on RAN translation reporters and organism survival.
Main Results:
- DENR knockdown significantly inhibited RAN translation of expanded GGGGCC and CGG repeat reporters.
- Reducing DENR levels improved survival in Drosophila models of GGGGCC repeat expansion.
Conclusions:
- Alternative initiation factors, particularly DENR, play a crucial role in RAN translation.
- These factors represent promising novel therapeutic targets for neurodegenerative conditions.
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