Cytosolic dopamine determines hypersensitivity to blunt force trauma
Kielen R. Zuurbier,
Rene Solano Fonseca,
Sonja L.B. Arneaud,
Lexus Tatge,
Gupse Otuzoglu,
Jordan M. Wall,
Peter M. Douglas
Affiliations
Kielen R. Zuurbier
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA
Rene Solano Fonseca
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Sonja L.B. Arneaud
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lexus Tatge
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Gupse Otuzoglu
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jordan M. Wall
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Peter M. Douglas
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; O’Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Summary: 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.
