Researchers from the Institute of Science Tokyo have made a groundbreaking discovery in the field of neurodegenerative disorders. Their study, recently published in the journal Nucleic Acids Research, sheds new light on the abnormal protein synthesis processes associated with diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
The study focused on the role of translation factors eIF1A and eIF5B in repressing the abnormal protein translation process linked to these neurodegenerative disorders. By using a human cell-free translation system, the researchers were able to reconstruct the aberrant translation of a mutated C9orf72 gene. This process revealed that eIF1A and eIF5B act at distinct checkpoints to suppress toxic protein synthesis, which is implicated in the pathology of ALS and FTD.
Neurodegenerative disorders are complex conditions with varied causes, but genetic defects, such as those seen in the C9orf72 gene, play a significant role in many inherited cases. The abnormal repetition of DNA sequences can trigger a process called repeat-associated non-AUG (RAN) translation, where protein synthesis starts from non-AUG codons instead of the conventional starting point. This leads to the production of toxic proteins that accumulate and contribute to neuronal damage.
Despite our understanding of the existence of these toxic proteins, the specific regulators of RAN translation have remained elusive. Traditional research methods using whole living cells often produce indirect results due to cellular responses, making it challenging to study the effects of translation factors accurately.
In this study, the research team led by Professor Hideki Taguchi took a bottom-up approach to identify key regulators of RAN translation. They successfully recreated the C9orf72-mediated RAN translation process in a controlled environment using a human factor-based reconstituted translation system. This system enabled the researchers to focus solely on non-AUG initiation mechanisms without interference from cellular side effects.
Through systematic screening, the researchers discovered that eIF1A and eIF5B act as repressors of RAN translation by enforcing strict control over non-canonical translation initiation at different checkpoints. Their findings provide detailed insights into how these translation factors regulate abnormal protein synthesis in neurodegenerative disorders.
By pinpointing eIF1A and eIF5B as key regulators of RAN translation, this study opens up new possibilities for developing therapeutic strategies against ALS and FTD. The researchers hope that their findings will pave the way for innovative treatments that target the underlying mechanisms of these devastating diseases.
