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

Autor:	Madhwani KR; Neuroscience Graduate Program, Brown University, Providence, RI 02912., Sayied S; Department of Neuroscience, Brown University, Providence, RI 02912., Ogata CH; Department of Biology, Brown University, Providence, RI 02912., Hogan CA; Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706., Lentini JM; Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY 14627., Mallik M; Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen 6525 AJ, The Netherlands., Dumouchel JL; Therapeutic Sciences Graduate Program, Brown University, Providence, RI 02912., Storkebaum E; Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen 6525 AJ, The Netherlands., Fu D; Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY 14627., O'Connor-Giles KM; Department of Neuroscience, Brown University, Providence, RI 02912.; Carney Institute for Brain Sciences, Brown University, Providence, RI 02912.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Nov 12; Vol. 121 (46), pp. e2317864121. Date of Electronic Publication: 2024 Nov 04.
DOI:	10.1073/pnas.2317864121
Abstrakt:	Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA-modifying enzyme that methylates wobble uridines in a subset of 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 reduced protein synthesis in the nervous system, including a specific decrease in selenoprotein levels. Either 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 null animals also exhibit associative memory impairments that are reversed by pharmacological antioxidant treatment. Together, these findings demonstrate the critical role of tRNA wobble uridine modification in redox homeostasis in the developing nervous system and reveal antioxidants as a potential therapy for ALKBH8-associated intellectual disability. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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