Panx1 deletion promotes synaptic reconfiguration and recruitment of cell death pathways in the Zebrafish MPTP model

Abstract

AbstractPannexin-1 (Panx1) channels have garnered attention for their implications in neurodegeneration, potentially with a role in mediating the delicate balance between cell death and survival. However, a comprehensive understanding of the underlying molecular and cellular mechanisms remains elusive, and whether Panx1 exhibits dual protective and toxic roles throughout the lifespan remains to be determined. To address these gaps, we focused on early-life changes in zebrafish larvae with impaired Panx1a function subjected to acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. We demonstrate that a single four-hour exposure to MPTP induces substantial alterations in locomotor behavior, the transcriptome, and local field potentials within the ascending visual pathway. KEGG pathway analysis underscored MPTP’s regulatory influence on neurodegeneration; here the differential expression of biomarkers for Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease, suggested a protective role of Panx1a ablation. However, the potential beneficial impact of targeting Panx1a is superseded by the deregulation of oxidative phosphorylation, glycolysis, ROS, hypoxia, unfolded protein response pathways, and reduced extracellular ATP. Notably, these changes correlate with a loss of synaptic neurotransmitter receptor and ion channel/transaporter expression and the differential expression of mTORC1, autophagy, and apoptosis signaling pathways. The resultant cell death was demonstrated by acridine orange dye uptake and in-vivo imaging, with a pronounced loss of cells observed in the pallium and tectum regions. Dual recordings of local field potentials across the optic tectum and pallium demonstrate Panx1a’s involvement in modulating local neuronal networks. Collectively, our results shed light on the impacts of acute MPTP treatment on locomotor behavior, transcriptomic shifts, metabolic disturbances, and the pivotal role of Panx1a in neurodegeneration and cell death. These insights enhance our comprehension of the intricate molecular and cellular mechanisms underpinning neurodegeneration, with implications for potential therapeutic strategies targeting Panx1 channels in the context of neuroinflammatory pathologies.Graphical AbstractHighlightsA genetic model was combined with the MPTP neurotoxin to explore the roles of zebrafish Pannexin-1 channels in neurodegeneration.A dysregulation of Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease biomarkers, suggested a protective role of Panx1a ablation.The potential beneficial impact of targeting Panx1a is superseded by synaptic plasticity loss, dysfunctional mitochondrial metabolism, and cell death.