tRNA fragments linked to Alzheimer’s disease

Summary: A new study identifies a crucial factor in brain aging and Alzheimer’s disease: the accumulation of Glu-5’tsRNA-CTC in neuronal mitochondria. This small RNA fragment disrupts mitochondrial protein synthesis and cristae structure, thereby accelerating cognitive decline and Alzheimer’s pathology.

By targeting these tRNA fragments with antisense oligonucleotides in aged mice, the researchers successfully reversed memory deficits, suggesting a potential new treatment strategy. This study highlights the important role that mitochondrial dysfunction plays in neurodegenerative diseases and paves the way for therapeutic interventions.

Highlights:

1. Accumulation of Glu-5’tsRNA-CTC in mitochondria impairs essential components of cellular energy production, thereby accelerating brain aging and Alzheimer’s disease.
2. Targeted intervention with antisense oligonucleotides in mice has been shown to alleviate learning and memory impairments associated with aging.
3. The study highlights the importance of maintaining mitochondrial function to prevent cognitive decline, providing new insights into the mechanisms of Alzheimer’s disease.

Source: University of Science and Technology of China

An important research article published in the journal Cellular metabolism by the team of Professor LIU Qiang from the University of Science and Technology of China (USTC) reveals the critical role of glutamate tRNA fragments in brain aging and Alzheimer’s disease.

The study revealed an age-dependent accumulation of Glu-5’tsRNA-CTC, a transfer RNA (tRNA)-derived small RNA, derived from nuclear-encoded tRNA in the mitochondria of glutaminergic neurons.

This abnormal accumulation impairs mitochondrial protein translation and cristae structure, ultimately accelerating the pathological processes of brain aging and Alzheimer’s disease.

Brain aging is an inevitable natural process that leads to a decline in cognitive functions. Alzheimer’s disease, a neurodegenerative disease, is the most common cause of dementia in older adults, where cognitive impairment is a hallmark feature of Alzheimer’s disease.

Mitochondria, known as the “powerhouses” of cells, provide energy to cells. Research has shown that mitochondrial dysfunction is closely associated with brain aging and Alzheimer’s disease.

Mitochondrial Glu-5’tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase 2 (LARS2), thereby impairing aminoacylation of mt-tRNALeu and translation of mitochondria-encoded proteins.

Defects in mitochondrial translation disrupt cristae architecture, leading to impaired glutaminase (GLS)-dependent glutamine formation and reduced synaptic glutamate levels.

Additionally, reduction of Glu-5’tsRNA-CTC may protect the aging brain from age-related defects in mitochondrial cristae, glutamine metabolism, synaptic structure, and memory.

LIU and his team shed light on the crucial role of glutamate tRNA fragments in brain aging and Alzheimer’s disease, providing new perspectives for delaying cognitive decline.

The researchers designed antisense oligonucleotides targeting these tRNA fragments and injected them into the brains of aged mice. This intervention significantly attenuated learning and memory deficits in aged mice.

In addition to elucidating the physiological role of normal mitochondrial cristae ultrastructure in maintaining glutamate levels, this study also defined the pathological role of transfer RNAs in brain aging and memory decline related to age.

About this Alzheimer’s disease research news

Author: Jane Fan
Source: University of Science and Technology of China
Contact: Jane Fan – University of Science and Technology of China
Picture: Image is credited to Neuroscience News

Original research: Free access.
“An aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting translation-dependent mitochondrial cristae organization” by Dingfeng Li et al. Cellular metabolism

Abstract

Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting translation-dependent mitochondrial cristae organization

Strong points

• Aging induces cytoplasmic localization of angiogenin to produce Glu-5′tsRNA-CTC
• Glu-5′tsRNA-CTC disrupts mitochondrial translation and cristae organization
• Crista ultrastructure is necessary for maintaining glutamate homeostasis in the brain
• ASO targeting Glu-5′tsRNA-CTC rescues memory decline in aged mice

Summary

Mitochondrial cristae, folds of the inner mitochondrial membrane, undergo aberrant changes in their architecture with age. However, the underlying molecular mechanisms and their contribution to brain aging remain largely elusive.

Here, we observe an age-dependent accumulation of Glu-5′tsRNA-CTC, a small RNA-derived transfer RNA (tRNA), derived from nuclear encoded tRNA.^Glue in the mitochondria of glutaminergic neurons.

Mitochondrial Glu-5′tsRNA-CTC disrupts mtRNA binding^Leu and leucyl-tRNA synthetase2 (LaRs2), altering mtRNA^Leu aminoacylation and translation of mitochondria-encoded proteins.

Defects in mitochondrial translation disrupt cristae organization, leading to damaged glutaminase (GLS)-dependent glutamate formation and reduced synaptosomal glutamate levels.

Furthermore, reduction of Glu-5′tsRNA-CTC protects aged brains from age-related defects in mitochondrial cristae organization, glutamate metabolism, synaptic structures, and memory.

Thus, beyond illustrating the physiological role of the normal ultrastructure of mitochondrial cristae in the maintenance of glutamate levels, our study defines the pathological role of tRNAs in brain aging and memory decline linked to age.