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Nerve cell protection genes that block the production of toxic proteins that cause Lou Gehrig’s disease discovered

Korean researchers have newly discovered a nerve cell protection gene that inhibits the production of toxic proteins in Lou Gehrig’s disease. Lou Gehrig’s disease is a representative degenerative brain disease in which toxic proteins accumulate in cells and nerve cells die.

Professor Lim Jung-hoon of UNIST’s Department of Bioscience discovered “ZNF598,” a gene that inhibits degenerative brain diseases such as Lou Gehrig’s disease and frontal lobe dementia, and identified a new molecular biological principle of nerve cell protection. This gene was found to inhibit apoptosis by removing toxic protein translation products in nerve cells of patients with Lou Gehrig’s disease. The results of this study are expected to be a new key to effective early diagnosis of degenerative brain diseases and development of fundamental brain disease treatments.

Protein is an essential substance for maintaining cell physiological phenomena and consists of amino acids. It is made through the transcription process of transferring protein (genetic) information stored in the form of a base sequence of DNA to mRNA and translation process in which polypeptide (connected structure of amino acid), a basic protein structure, is created from the transcribed protein cipher. A protein is produced in which polypeptides that have undergone a translation process can perform special functions through three-dimensional structural folding. The mRNA vaccine also makes viral antigens with the same principle.

Professor Lim’s research team activated the ZNF598 gene to suppress the death of nerve cells derived from Lou Gehrig’s disease. ZNF598 performed this function through the protein translation quality management pathway. Protein translation quality management is a process of recognizing and decomposing abnormally produced translation intermediates. When the ribosome in charge of protein translation stops during the abnormal translation process (ribosome stagnation), the protein translation quality control path is activated, and the translation product is separated from the ribosome and decomposed. Studies have shown that the toxic protein of Lou Gehrig’s disease causes ribosome stagnation.

In this study, the research team confirmed that in motor neurons differentiated from induced pluripotent stem cells in patients with Lou Gehrig’s disease, major genes involved in protein translation quality management, such as ZNF598, are abnormally expressed, resulting in poor protein translation quality management.

It is expected that the functional analysis and control technology of protein translation quality management will make a new breakthrough in the prediction, diagnosis, and treatment technology development of related diseases such as Lou Gehrig’s disease and prefrontal dementia.

Reference Journal: Park J, Lee J, Kim JH, Lee J, Park H, Lim C. ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD. Nucleic Acids Res. 2021 Sep 22:gkab834. doi: 10.1093/nar/gkab834. Epub ahead of print. PMID: 34551427.

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