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Home » National University Corporation Kumamoto University Elucidating the mechanism by which enzymes that modify transfer RNA support brain function – Toward understanding the general principles of brain diseases caused by deletion of RNA modification –

National University Corporation Kumamoto University Elucidating the mechanism by which enzymes that modify transfer RNA support brain function – Toward understanding the general principles of brain diseases caused by deletion of RNA modification –

National University Corporation Kumamoto University
Elucidating the mechanism by which enzymes that modify transfer RNA support brain function – Understanding the general principles of brain diseases caused by deletion of RNA modification –
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・We discovered that when the transfer RNA*1 methylation*2 enzyme “TRMT10A” is lost, the amount of specific transfer RNA decreases throughout the body.
・We found that loss of TRMT10A disrupts the synthesis of nerve-related proteins in the brain, causing abnormalities in synaptic structure and function, leading to a decline in brain tissue function.
・Research to elucidate the general principles of “RNA modification diseases” such as intellectual disability and epilepsy that occur due to loss of transfer RNA modification*3, and its application is expected to have a ripple effect on future treatments for brain diseases. will be done.
[Summary explanation]
A research team of Professor Kazuhito Tomizawa, Lecturer Takeshi Nakajo, and then graduate student Roland Tresky of the Graduate School of Life Sciences at Kumamoto University discovered that mutations in TRMT10A, a type of enzyme that modifies transfer RNA (tRNA), can cause intellectual disability. We have elucidated the mechanism by which this occurs. Deletion of various tRNA-modifying enzymes causes intellectual disability, but until now the detailed mechanism of onset has remained largely unknown, and this may lead to future advances in the treatment of intellectual disability. The results of this research were published in the British scientific journal “Nucleic Acids Research” on Tuesday, July 2, 2024, at 9:01 a.m. Japan time. This research is supported by the Japan Science and Technology Agency (JST) Emergent Research Support Project “Emergence of RNA Modification Editing Technology and Its Application to Treatment” (Project Number: JPMJFR204Z, Principal Investigator: Takeshi Nakajo) and the Japan Society for the Promotion of Science Scientific Research. This work was carried out with the support of financial aid projects (problem number: 20H03187, principal investigator: Takeshi Nakajo), etc. [Future development] It is known that loss of even one of the approximately 30 proteins responsible for modifying tRNA causes brain and neurological diseases, but the detailed mechanism of onset is largely unknown. It was. The research group previously elucidated the mechanism by which deficiency of another tRNA methyltransferase (FTSJ1*4) causes intellectual disability (Nagayoshi, Chujo, Tomizawa et al. 2021). When TRMT10A-deficient mice and FTSJ1-deficient mice are compared, both have (1) a decrease in the amount of a specific tRNA and a decrease in translation of the genetic code by that tRNA, (2) abnormalities in synaptic structure and function, (3) A decline in brain tissue function and maintenance of other tissue functions was observed. On the other hand, the difference between TRMT10A-deficient mice and FTSJ1-deficient mice is that in FTSJ1-deficient mice, specific tRNAs are decreased only in the brain, whereas in
TRMT10A-deficient mice, tRNAs are decreased throughout the body. The results of this research clearly show that even when the amount of tRNA decreases throughout the body, brain tissue function is particularly susceptible to decline compared to other tissues. In the future, we will investigate whether suppressing the decrease in the amount of tRNA in the brain can suppress the decline in brain tissue function even if the modification is lost, and in the future, we will aim to treat intellectual disabilities caused by the deletion of tRNA modification. It is expected that this will lead to.
[Term explanation] *1. Transfer RNA (tRNA): An adapter molecule that connects genetic information (nucleic acid sequences) and substances (amino acids), and is composed of a substance called RNA. tRNA enters the ribosome, which is a protein synthesis machine, and is responsible for decoding genetic information and delivering amino acids to proteins that are being synthesized. *2. Methylation: A chemical reaction that imparts a methyl group consisting of one carbon and three hydrogens. Inside the cell, enzymes methylate tRNA. *3. Modification: A chemical structure added to the bases and sugars that make up RNA. There are various types of modifications such as methylation, sulfation, and addition of amino acids. Modifications are made by one or more enzymes.
*4. FTSJ1: An enzyme that methylates the 32nd and 34th bases of tRNA. Qualification of FTSJ1
Loss of function causes intellectual disability in humans.
[Paper information]
Paper title: TRMT10A dysfunction perturbs codon translation of initiator methionine and glutamine and impairs brain functions in mice Authors: Roland Treski1, Yuta Miyamoto1, Yoshitomo Naga1, Tadashi Yabuki2, Kimi Araki3, Yukie Takahashi1, Yoshihiro Kobara1, Keisō Kuzu1, Shioriyo Nishiguchi1, Koichi Fukuda1, Hitomi Kaneko1, Nobuko Maeda 1, Nin Matsuura 1, Shintaro Iwasaki 4, Mitsunori Sakakida 1, Michiji Shioda 2, Ken Wei 5, Kazuhito Tomizawa 1, Takeshi Nakajo 1 (1 Kumamoto University Graduate School of Life Science (Medical), 2 Kumamoto University Department of Embryonic Medicine Research Institute, 3 Kumamoto University Life Resources Research and Support Center, 4 RIKEN, 5 Tohoku University Institute of Aging and Aging) Journal: Nucleic Acids Research (international academic journal of molecular biology)
doi: 10.1093/nar/gkae520
URL: https://doi.org/10.1093/nar/gkae520
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