Description
- Abstract:
- Precise and dynamic regulation of protein expression is required for neural development and function. During protein synthesis, mRNA decoding is facilitated by transfer RNAs (tRNAs) that are extensively post-transcriptionally modified to promote structural stability and accurate decoding. While a growing number of rare neurodevelopmental disorders linked to tRNA modifying enzymes have been reported, the effect on nervous system development and function are poorly understood. I initially describe known tRNA methyltransferase modifications in the context of a broad sense of disease with a focus on modifying enzymes with overlapping links to cancer biology and neurodevelopmental disorders, focusing specifically on tRNA methyltransferases. I also discuss new treatment avenues, including the prospect of regulating translation through tRNA therapeutics or the targeting of tRNA modifying enzymes. The conservation of the tRNA methyltransferase family between Drosophila and human yields an exciting opportunity to study the impact of tRNA modifications in the nervous system development and function in Drosophila, a tractable in vivo model organism. I detail our work that identifies putative tRNA methyltransferase 9B (TRMT9B), one of two metazon homologs of yeast tRNA wobble uridine methyltransferase 9 (Trm9), as a negative regulator of synaptic growth and function. I then detail my studies of tRNA methyltransferase 1 (TRMT1), which has recently been linked to intellectual disability, and find it functions in ensheathing glia to promote synapse formation and memory. Finally, I discuss the impact of tRNA methylation on neuronal translation, our ongoing studies to identify critical downstream targets, and future directions for building mechanistic understanding and developing therapeutics for rare disorders associated with disrupted tRNA methylation.
- Notes:
- Thesis (Ph. D.)--Brown University, 2025
Citation
Dumouchel, Jennifer L.,
"Role of tRNA methyltransferases in nervous system development and function"
(2025).
Therapeutic Sciences.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:7apudtze/
