Cytosolic dopamine determines hypersensitivity to blunt force trauma [N2 injury timeline]

The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is a conserved phenomenon across species, extending from nematodes to humans. However, the molecular mechanisms contributing to this hypersensitivity to blunt force injury remain poorly understood. We find that dopamine oxidation, a key driver of Parkinson's Disease, extends its toxic role to the acute challenges of blunt force trauma. Ectopic synthesis of dopamine in serotonergic neurons alone proves sufficient in determining neuronal subtype sensitivity to trauma-induced death. While dopaminergic neurons maintain this neurotransmitter in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Perturbing dopamine synthesis and its packaging into synaptic vesicles further demonstrate how cytosolic dopamine is both necessary and sufficient to drive cell loss upon mechanical stress and during aging. Additionally, trauma activates the B-Zip transcription factor, fos-1, which exacerbates this toxic cascade by transcriptionally upregulating the rate-limiting enzyme in dopamine synthesis, cat-2. In summary, our study unravels the molecular intricacies that render dopaminergic neurons uniquely prone to physical perturbation, highlighting a shared vulnerability across different evolutionary lines. Overall design: Day 1 adult N2 worms were subjected to mechanical trauma (8600 RPM, 16s) and placed on recovery plates. Worms were collected in Trizol 8, 48, and 96 hours after injury. To prevent progeny contamination worms were kept sterile by maintaining all conditions on cdc-25.1 RNAi.