Urea Cycle Dysregulation Drives Metabolic Stress and Neurodegeneration in Parkinson’s Disease

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Abstract Parkinson's disease (PD) is a common neurodegenerative disease characterized by a decrease in the number of dopaminergic neurons in the substantia nigra, depletion of dopamine in the striatum, and accumulation of α-synuclein fibrils in Lewy bodies. However, the underlying mechanisms PD pathogenesis remain elusive. Emerging evidence suggests that dysregulated urea metabolism may play a central role in neurodegeneration. In this study, we found significantly elevated serum urea levels in PD patients, accompanied by upregulation of key urea cycle enzymes. In MPTP-induced PD mice, urea levels were increased in the substantia nigra and striatum, alongside marked activation of urea cycle enzymes (ODC1, ARG1, OTC) and urea transporter UT-B. Mechanistically, brain urea accumulation likely results from imbalanced urea cycle activity and impaired UT-B-mediated clearance, with region-specific compensatory upregulation of UT-B in the substantia nigra. In vitro experiments further demonstrated that MPTP-treated neuronal cells exhibited enhanced expression of urea cycle enzymes and UT-B, while high urea directly induced dopaminergic dysfunction, manifesting as suppression of tyrosine hydroxylase (TH) expression. Crucially, knockdown of ODC1 reversed urea metabolic dysregulation, restored TH expression, and alleviated dopaminergic neuronal damage in PD cell models. This study reveals urea cycle dysregulation as a core metabolic feature of PD, driven by ODC1-mediated urea metabolic reprogramming, and proposes targeting ODC1 or urea metabolism as a novel therapeutic strategy for PD.

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