Cytosolic dopamine determines hypersensitivity to blunt force trauma

• Published in: iScience Vol. 27; no. 6; p. 110094
• Main Authors: Zuurbier, Kielen R., Solano Fonseca, Rene, Arneaud, Sonja L.B., Tatge, Lexus, Otuzoglu, Gupse, Wall, Jordan M., Douglas, Peter M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.06.2024; Elsevier
• Subjects: molecular neuroscience; neuroscience; molecular neuroscience; neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110094

The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is conserved across species, from nematodes to humans. However, the molecular mechanisms underlying this hypersensitivity to blunt force trauma remain elusive. We find that extravesicular dopamine, a key driver of Parkinson’s disease, extends its toxic role to the acute challenges associated with injury. Ectopic dopamine synthesis in serotonergic neurons sensitizes this resilient neuronal subtype to trauma-induced degeneration. While dopaminergic neurons normally maintain dopamine in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Cytosolic dopamine accumulation, through perturbations to its synthesis, metabolism, or packaging, is necessary and sufficient to drive neurodegeneration upon injury and during aging. Additionally, degeneration is further exacerbated by rapid upregulation of the rate-limiting enzyme in dopamine synthesis, cat-2, via the FOS-1 transcription factor. Fundamentally, our study in C. elegans unravels the molecular intricacies rendering dopaminergic neurons uniquely prone to physical perturbation across evolutionary lines. [Display omitted] •Trauma resistant neurons can be sensitized through ectopic dopamine synthesis•Dopaminergic neurons experience excessive oxidative stress upon blunt force trauma•Mitochondrial calcium buffering and cytosolic dopamine synergistically drive ROS•FOS-1 dependent activation of dopamine synthesis upon trauma worsens degeneration Molecular neuroscience; Neuroscience