753B Poster - 12. Physiology, metabolism and aging
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Matanel Yheskel; Julie Secombe

Affiliation: Albert Einstein College of Medicine

Keywords:
b. metabolism; t. other (Neuronal Translational Control)

KDM5 is a histone lysine demethylase responsible for the demethylation of H3K4me3, a histone modification associated with transcriptionally active promoters. Mutations in three of the four KDM5 paralogs in humans (KDM5A-C) are associated with intellectual disability but KDM5’s role in regulating neuronal function is unknown. RNA-Sequencing of neuron-specific kdm5 knockdown flies reveals that the majority of ribosome protein genes (RPG) are downregulated compared to control, however there is no dramatic change to bulk translation or translation initiation. Changes in RP stoichiometry has been shown to affect translation efficiency (TE) of different classes of mRNA; to that end, we performed ribosomal profiling in kdm5 knockdown neurons. This analysis revealed that mRNAs encoding proteins with roles in glycolysis, the tri-carboxylic acid (TCA) cycle, and fatty acid metabolism showed significantly reduced TE in kdm5 knockdown neurons. Interestingly, this included genes whose human homologs are implicated in neurological disorders. These data reveal a novel role of KDM5 in the translational regulation of key metabolic pathways necessary for proper neuronal homeostasis and function.