Researchers Identify Key Regulators in Neurodegenerative Disorders

A recent study from researchers at Science Tokyo has made significant strides in understanding the molecular mechanisms behind neurodegenerative disorders. They have reconstructed the abnormal protein translation process associated with the mutated C9orf72 gene, shedding light on its role in conditions such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The findings are published in the journal Nucleic Acids Research.

Neurodegenerative disorders remain a critical challenge in medicine, with many of their underlying causes still not fully understood. A common theme in various inherited cases is the abnormal repetition of DNA sequences. Such genetic defects can lead to a cellular process called repeat-associated non-AUG (RAN) translation. This process deviates from standard protein synthesis by initiating from non-AUG codons, generating toxic proteins that accumulate and contribute to neuronal damage.

Despite existing knowledge about the toxic proteins produced, the specific regulators involved in RAN translation have largely remained elusive. Traditional research methods often rely on whole living cells, which can obscure results due to indirect cellular responses. In response to this challenge, a team led by Professor Hideki Taguchi of Science Tokyo employed a novel approach to discern these key regulatory factors.

Unveiling Key Translation Factors

The research team successfully replicated the RAN translation process associated with the mutated C9orf72 gene using a human cell-free translation system known as the human PURE system. Developed by scientists from the University of Hyogo, this innovative system utilizes highly purified human translation components to accurately reproduce the RAN translation process outside of living cells. This allowed the researchers to eliminate cellular side effects and focus solely on the initiation mechanisms of non-AUG translation.

Through systematic screening, the team discovered that two canonical translation initiation factors, eIF1A and eIF5B, act as repressors of RAN translation. Their findings indicate that these factors maintain strict control over non-canonical translation initiation at two key checkpoints. Specifically, eIF1A suppresses C9-RAN translation during the scanning phase by facilitating the correct selection of the start codon, while eIF5B enforces translational control in the post-scanning phase, during ribosomal subunit assembly.

“The successful in vitro reconstitution of abnormal protein synthesis enabled the detailed elucidation of the mechanisms of action of eIF1A and eIF5B,” stated Professor Taguchi.

The researchers validated their findings in human cells, confirming that eIF1A and eIF5B independently and additively repress RAN translation. Notably, they found that when cells experience stress, C9-RAN translation typically increases. However, this increase was entirely abolished in the absence of eIF1A, underscoring its vital role in the integrated stress response and its enhancement of C9-RAN translation.

Implications for Future Research

By identifying eIF1A and eIF5B as crucial regulators, this study provides valuable insights into the mechanisms underlying ALS and FTD. These findings pave the way for potential therapeutic strategies aimed at controlling RAN translation, which could lead to novel treatments for these devastating neurodegenerative diseases.

“These newfound insights provide a foundation for developing technologies to control RAN translation, paving the way for novel therapeutic strategies against neurodegenerative diseases,” concluded Professor Taguchi, expressing optimism about future research efforts.

The implications of this research extend beyond laboratory findings, offering a glimpse into potential clinical applications that could significantly impact the lives of those affected by neurodegenerative conditions. Further exploration of these mechanisms will be essential in the ongoing quest to unravel the complexities of diseases like ALS and FTD.