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

Autor:	Madhwani KR; Neuroscience Graduate Program, Brown University, Providence, RI, USA., Sayied S; Department of Neuroscience, Brown University, Providence, RI, USA., Ogata CH; Department of Biology, Brown University, Providence, RI, USA., Hogan CA; Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI, USA., Lentini JM; Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USA., Mallik M; Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, NL., Dumouchel JL; Therapeutic Sciences Graduate Program, Brown University, Providence, RI, USA., Storkebaum E; Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, NL., Fu D; Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USA., O'Connor-Giles KM; Department of Neuroscience, Brown University, Providence, RI, USA.; Carney Institute for Brain Sciences, Brown University, Providence, RI, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 14. Date of Electronic Publication: 2023 Nov 14.
DOI:	10.1101/2023.11.14.566895
Abstrakt:	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. Through in vivo studies in Drosophila , we show that ALKBH8 controls oxidative stress in the brain to restrain synaptic growth and support learning and memory. ALKBH8 null animals lack wobble uridine methylation and exhibit a global reduction in protein synthesis, including a specific decrease in selenoprotein levels. Loss of ALKBH8 or independent disruption of selenoprotein synthesis results in ectopic synapse formation. Genetic expression of antioxidant enzymes fully suppresses synaptic overgrowth in ALKBH8 null animals, confirming oxidative stress as the underlying cause of dysregulation. ALKBH8 animals 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. Competing Interests: Competing Interest Statement: The authors declare that they have no conflict of interest.
Databáze:	MEDLINE
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