Neurodevelopmental role of a tRNA methyltransferase underlying intellectual disability

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PROJECT SUMMARY Gene regulation at multiple levels is critical for nervous system development and function. A number of mutations leading to global dysregulation of gene expression have been found to disproportionately affect the nervous system, leading to neurodevelopmental and neurodegenerative disorders. Transfer RNAs (tRNAs), which recognize codons and add the appropriate amino acid to growing polypeptides, can dynamically regulate translation. tRNAs are heavily post-transcriptionally modified to regulate their structure, stability, and fidelity. ALKBH8 is one of two metazoan homologs of the yeast tRNA methyltransferase TRM9. Stop and missense mutations in human ALKBH8 have recently been shown to cause intellectual disability in four families. However, ALKBH8’s role in the nervous system remains unknown. To address this, I have generated null alleles in Drosophila and found that ALKBH8 regulates synapse formation. My preliminary data suggest ALKBH8 attenuates synaptic growth by limiting oxidative stress through the methylation of tRNA- selenocysteine, which yields the rare 21st amino acid selenocysteine for the synthesis of selenoproteins. In AIM 1, I will employ genetic, pharmacological, imaging, and bioinformatic approaches in Drosophila to define the links between ALKBH8, selenoproteins, and synaptic growth and investigate the impact of a human ALKBH8 mutation in the nervous system. In AIM 2, I will build on the skills gained during my dissertation work by expanding into human-derived pluripotent stem cells (iPSCs) to model neurological disorders and probe potential treatment strategies. The proposed experimental plan will provide mechanistic insight into how tRNA modifications regulate gene expression during nervous system development. The proposed training plan will provide me with the technical, academic, and professional skillset to thrive for the remainder of my predoctoral training and beyond as I transition into a postdoctoral position. Successful completion of the F99/K00 aims will place me in a unique position to investigate mechanisms underlying neurodevelopment disorders in two model systems with complementary strengths and identify potential therapeutic treatments for affected individuals.