Summary: New research reveals that lack of the TRMT10A enzyme disrupts tRNA levels, leading to impaired protein synthesis and brain function. Researchers found that mice lacking the Trmt10a gene had reduced levels of a key tRNA, which affects neuronal synapses and cognitive performance.
The findings suggest that although tRNA loss occurs in multiple tissues, the brain is particularly susceptible. This study could pave the way for new therapies targeting tRNA modifications to treat intellectual disabilities.
Important facts:
Deficiency of TRMT10A reduces key tRNA levels and affects brain protein synthesis. Mice lacking Trmt10a have impaired synaptic function and cognitive performance. This study highlights the potential for new therapeutics targeting tRNA modification.
Source: Kumamoto University
A groundbreaking study conducted by a research team at Kumamoto University has revealed the important role of the tRNA methyltransferase TRMT10A in supporting brain function.
The findings revealed how lack of TRMT10A leads to reduced levels of specific transfer RNA (tRNA), disrupting protein synthesis in the brain and impairing synaptic structure and function.
The research group created mice lacking the Trmt10a gene and measured tRNA levels in the brain. They found that two types of tRNAs, the initiator methionine tRNA and a specific glutamine tRNA, which are essential for the initiation of protein synthesis, were significantly reduced. This reduction resulted in decreased protein synthesis of important genes in the brain, particularly those related to neurological function.
As a result, the structural integrity and plasticity of synapses, which are essential for learning and memory, were compromised, impairing the mice’s cognitive performance.
Remarkably, while reduced tRNA levels of the initiators methionine and glutamine were observed throughout various tissues, the dysfunction was confined to the brain, indicating its special vulnerability. .
Takeshi Nakajo, a lecturer at Kumamoto University’s Faculty of Life Sciences, who led the research, said, “A similar decrease in tRNA levels was observed in human cells lacking TRMT10A, indicating that the mechanism discovered in mice is likely to apply to humans. It suggests that.” ”
This study highlights the importance of universal tRNA modifications in the translation of specific codons. Based on these insights, the research team investigated whether preventing the decline in tRNA levels in the brain could alleviate functional impairment, leading to new therapies to treat intellectual disability caused by tRNA modification defects. We aim to find out if there is a possibility that this could lead to
This research not only advances our understanding of RNA-modifying diseases but also opens the door to innovative strategies to address the cognitive challenges associated with these diseases.
About this genetics and synaptic plasticity research news
Author: Nuo Li
Source: Kumamoto University
Contact: Nuo LI – Kumamoto University
Image: Image credited to Neuroscience News
Original research: Open access.
“TRMT10A dysfunction disrupts initiator methionine and glutamine codon translation and impairs brain function in mice” (Takeshi Chujo et al.) Nucleic acid research
abstract
TRMT10A dysfunction disrupts initiator methionine and glutamine codon translation and impairs brain function in mice
In higher eukaryotes, tRNA methyltransferase 10A (TRMT10A) is responsible for N1 methylguanosine modification at position 9 of various cytoplasmic tRNAs.
Pathogenic mutations in TRMT10A cause intellectual disability, microcephaly, diabetes, and short stature in humans and produce cytotoxic tRNA fragments in cultured cells. However, it is not clear how TRMT10A supports codon translation and brain function.
Here, we generated Trmt10a null mice and showed that tRNAGln(CUG) and initiator methionine tRNA levels are universally reduced in various tissues. The same was true for human cell lines lacking TRMT10A.
Ribosome profiling in mouse brain reveals that TRMT10A dysfunction causes ribosome slowing at the Gln (CAG) codon and increases Atf4 translation due to a higher frequency of leaky scanning of upstream open reading frames. It became.
Broadly speaking, translation of a subset of mRNAs, particularly of neural structures, is disrupted in mutant brains.
Although Trmt10a null mice showed no discernible defects in the pancreas, liver, or kidney, they had lower body weight and exhibited smaller postsynaptic density in the hippocampus, which is associated with defects in synaptic plasticity and memory.
Taken together, our studies provide mechanistic insight into the role of TRMT10A in the brain and illustrate the importance of universal tRNA modifications during translation of specific codons.