Deciphering the role of the DCC/UNC-40 receptor in dopaminergic neurons during health and disease
TheUNC-40 receptor, a homolog of the human DCC receptor, is critical for neuronal development and maintenance, with its dysregulation implicated in neurodegenerative diseases such as Parkinson’s disease. This study investigates the role of UNC-40 in dopaminergic neuron health and degeneration using Caenorhabditis elegans as a model system. Loss-of-function mutations in UNC-40 conferred resistance to 6-hydroxydopamine (6-OHDA)-induced DA neuron degeneration, while stabilization of UNC-40 via mutation in the CPD regulatory site led to spontaneous, selective DA neurodegeneration independent of toxins. Mechanistic analyses revealed that UNC-40 stabilization triggers parthanatos, a caspase-independent cell death pathway driven by mitochondrial oxidative stress. Pharmacological inhibition of PARP-1 and treatment with mitochondrial antioxidants significantly rescued DA neurons from degeneration.suggesting UNC-40 stabilization causes mitochondrial oxidative stress. Remarkably, UNC-40-induced degeneration was sexually dimorphic, affecting hermaphrodites but not males. Transcriptomic analyses revealed significant gene expression changes in hermaphrodites carrying stabilized UNC40, while males exhibited minimal changes, suggesting intrinsic protective mechanisms. UNC-6, a ligand for UNC-40, was identified as a critical external factor modulating this dimorphism; its absence in hermaphrodites rendered them vulnerable, while its presence in males made them unaffected by the stabilization of the receptor. Behavioral assays revealed functional impairments in hermaphrodites with stabilized UNC-40, linked to altered synaptic activity and excitotoxicity. These findings establish UNC-40 as a key regulator of DA neuron health, highlight its role in oxidative stress and synaptic maintenance, and underscore sexually dimorphic vulnerability to neurodegeneration. The parallels between UNC-40 in C. elegans and DCC in humans suggest conserved mechanisms underlying neurodegeneration and point to potential therapeutic targets for diseases like PD.