tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory

Abstract

Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA modifying enzyme that methylates wobble uridines in specific tRNAs to modulate translation. Through methylation of tRNA-selenocysteine, ALKBH8 promotes selenoprotein synthesis and regulates redox homeostasis. Pathogenic variants in ALKBH8 have been linked to intellectual disability disorders in the human population, but the role of ALKBH8 in the nervous system is unknown. Throughin vivostudies inDrosophila, we show that ALKBH8 controls oxidative stress in the brain to restrain synaptic growth and support learning and memory.ALKBH8null animals lack wobble uridine methylation and exhibit a global reduction in protein synthesis, including a specific decrease in selenoprotein levels. Loss ofALKBH8or independent disruption of selenoprotein synthesis results in ectopic synapse formation. Genetic expression of antioxidant enzymes fully suppresses synaptic overgrowth inALKBH8null animals, confirming oxidative stress as the underlying cause of dysregulation.ALKBH8animals also exhibit associative learning and memory impairments that are reversed by pharmacological antioxidant treatment. Together, these findings demonstrate the critical role of tRNA modification in redox homeostasis in the nervous system and reveal antioxidants as a potential therapy for ALKBH8-associated intellectual disability.Significance StatementtRNA modifying enzymes are emerging as important regulators of nervous system development and function due to their growing links to neurological disorders. Yet, their roles in the nervous system remain largely elusive. Throughin vivostudies inDrosophila, we link tRNA methyltransferase-regulated selenoprotein synthesis to synapse development and associative memory. These findings demonstrate the key role of tRNA modifiers in redox homeostasis during nervous system development and highlight the potential therapeutic benefit of antioxidant-based therapies for cognitive disorders linked to dysregulation of tRNA modification.

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

“…From these analyses, we identified the tRNA-methyltransferase AlkBH8 as a potential novel therapeutic target in CRC, as high AlkBH8 expression correlates with decreased overall survival in CRC patients (Figure 5A-B). AlkBH8 has been extensively reported to regulate the selenoproteome via methylation of tRNA-selenocysteine, with AlkBH8 knockdown and knockout models demonstrating a decreased ability to translate selenoproteins [54][55][56][57][58][59][60][61] . We observed that AlkBH8 expression is significantly increased in tumor tissue as compared to normal controls (Figure 5C), and that patients with early-onset CRC have increased expression of AlkBH8 as compared to all other age groups (Figure 5D).…”