Drosophila probosis extension reflex assay
Gustatory Memory in Drosophila
About
Intellectual disability (ID) affects ~1–3% of the global population and is especially prevalent in regions with high rates of consanguinity, highlighting the need to identify underlying autosomal recessive genetic causes
TRMT1 was identified as a novel ID-associated gene through genome-wide linkage analysis and sequencing of affected families in Iran, revealing a homozygous 2-bp deletion that disrupts gene function
TRMT1 encodes a tRNA methyltransferase responsible for adding the modification N²,N²-dimethylguanosine (m²,²G) at position 26 of many tRNAs, a modification critical for proper tRNA folding and stability
Loss of TRMT1 function leads to defective tRNA modification, impaired RNA binding, and altered protein translation, with reduced cytoplasmic translation but increased mitochondrial translation
TRMT1-deficient cells show disrupted redox homeostasis, including elevated reactive oxygen species (ROS) and hypersensitivity to oxidative stress, indicating a previously unrecognized role for tRNA modifications in cellular stress regulation
Even partial knockdown of TRMT1 in human neural progenitor cells is sufficient to increase oxidative stress sensitivity, linking TRMT1 dysfunction directly to neuronal vulnerability
These findings suggest that TRMT1-associated ID arises from widespread cellular instability, rather than a single developmental defect, affecting translation, metabolism, and neuronal resilience
Drosophila melanogaster offers a powerful in vivo model to study TRMT1, as ~60% of human disease genes have fly homologs and synaptic biology is highly conserved
Proposed in vivo studies aim to determine:
- Where and when TRMT1 is expressed in the nervous system
- How TRMT1 loss affects synapse structure and function
- Whether TRMT1 dysfunction impairs learning and memory, core features of intellectual disability
Together, this work reframes tRNA modifications as active regulators of neuronal health, with implications for neurodevelopment, cognition, and vulnerability to cellular stress
