Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection

Abstract

Neurons rely on tightly regulated metabolic networks to sustain their high-energy demands, particularly through the coupling of glycolysis and oxidative phosphorylation. Here, we investigate the role of pyruvate kinase (PyK), a key glycolytic enzyme, in maintaining axonal and synaptic integrity in the Drosophila melanogaster neuromuscular system. Using genetic deficiencies in PyK, we show that disrupting glycolysis induces progressive synaptic and axonal degeneration and severe locomotor deficits. These effects require the conserved dual leucine zipper kinase (DLK), Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) Fos transcription factor axonal damage signaling pathway and the SARM1 NADase enzyme, a key driver of axonal degeneration. As both DLK and SARM1 regulate degeneration of injured axons (Wallerian degeneration), we probed the effect of PyK loss on this process. Consistent with the idea that metabolic shifts may influence neuronal resilience in context-dependent ways, we find that pyk knockdown delays Wallerian degeneration following nerve injury, suggesting that reducing glycolytic flux can promote axon survival under stress conditions. This protective effect is partially blocked by DLK knockdown and fully abolished by SARM1 overexpression. Together, our findings help bridge metabolism and neurodegenerative signaling by demonstrating that glycolytic perturbations causally activate stress response pathways that dictate the balance between protection and degeneration depending on the systems state. These results provide a mechanistic framework for understanding metabolic contributions to neurodegeneration and highlight the potential of metabolism as a target for therapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/647282v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1bba464org.highwire.dtl.DTLVardef@25bdd2org.highwire.dtl.DTLVardef@1d12611org.highwire.dtl.DTLVardef@1a3d96_HPS_FORMAT_FIGEXP M_FIG C_FIG