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Polyamine Metabolites Revealed by Zebrafish Optic Nerve Regenerative Metabolomics and Their Effect on Neurite Outgrowth in Murine Retinal Ganglion Cells
Location: 47
Mentor: Dr. Sanjoy Bhattacharya
Zebrafish (Danio rerio) exhibit a remarkable ability to regenerate their adult optic nerve, unlike mammals, which experience irreversible neurodegeneration. Despite the potential for translational regenerative therapies, untargeted metabolomic studies of successful regenerative models are limited. This study conducted metabolomic profiling of regenerating zebrafish retinal and optic nerve tissues to identify relevant metabolic pathways that could inform therapeutic strategies for mammalian regeneration. At 3 days post-injury (dpi), upregulation of arginine and polyamine metabolism was observed, with increased levels of N1-acetylspermidine. The polyamine pathway, previously linked to regeneration in both fish and mammalian systems, has not been thoroughly investigated in the context of acetylated polyamines and their effects on axonal growth. In vitro assays revealed that retinal ganglion cells (RGCs) preferentially utilize ornithine, putrescine, and spermidine for axonal growth over acetylated polyamines. Furthermore, inhibiting polyamine oxidase (PAOX), which converts acetylated polyamines back to their non-acetylated forms, significantly impaired RGC neurite outgrowth. Proteomic analysis of polyamine-treated RGCs found reduced proteins predominantly in the nucleus and involved in cell organization/biogenesis and mortality pathways. In vivo studies demonstrated that PAOX and SAT1 show opposing trends after optic nerve injury, with PAOX localized near the injury site and overlapping with microglial markers. These findings suggest that microglial cells may play a role in replenishing polyamine stores during nerve injury. Imaging Mass Spectrometry (IMS) further confirmed the localization of putrescine and spermidine near the injury site. The data underscores the importance of polyamine metabolism in optic nerve regeneration, highlighting new pathways for future regenerative therapies.
