National Institute of Neurological Disorders and Stroke 5R01NS119525-05

The Function of the Cytoplasmic tRNA Repertoire in the Cellular and Molecular Homeostasis of the Mammalian Brain

This NIH-funded project investigates the role of cytoplasmic tRNA genes in brain cellular and molecular homeostasis, focusing on how mutations in specific tRNA genes affect neuronal function and disease mechanisms.

Description

Transfer RNAs (tRNAs) are critical adaptor molecules that physically link amino acids to codons, decoding mRNA transcripts during translation. The mammalian genome contains hundreds of tRNA genes which are classified into families based on their anticodon. Each family contains multiple tRNA genes, suggesting that these genes may be buffered against the impact of deleterious mutations. Recent studies demonstrate that mutation impairing processing of n-Tr20, a tRNAArgUCU gene, or its complete loss, alters gene expression and physiological responses at cellular and organismal levels, despite the existence of other functional tRNAArgUCU genes. Loss of n-Tr20 decreases seizure susceptibility and alters hippocampal excitatory-inhibitory balance, leading to ribosome stalling on cognate AGA codons, decreased mTORC1 signaling, and activation of stress responses. Overexpression of other tRNAArgUCU family members restores seizure susceptibility, indicating phenotypes are due to decreased neuronal tRNA pool. The project aims to elucidate cellular mechanisms underlying these effects, including conditional deletion of n-Tr20 in inhibitory or excitatory neurons, analysis of translatome changes, and investigation of tRNA depletion impacts across cell types, extending findings into human iPSC-derived neurons.

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