Urea cycle dysregulation drives metabolic stress and neurodegeneration in Parkinson’s disease
Abstract Parkinson’s disease (PD), common neurodegenerative disorder, involves substantia nigra dopaminergic neuron loss and α-synuclein accumulation in Lewy bodies. While pathogenesis remains unclear, dysregulated urea metabolism may play a central role. This study detected elevated serum urea leve...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-01099-5 |
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| Summary: | Abstract Parkinson’s disease (PD), common neurodegenerative disorder, involves substantia nigra dopaminergic neuron loss and α-synuclein accumulation in Lewy bodies. While pathogenesis remains unclear, dysregulated urea metabolism may play a central role. This study detected elevated serum urea levels in PD patients with upregulated urea cycle enzymes. In MPTP-induced PD mice, urea accumulated in the substantia nigra and striatum, alongside increased activity of urea cycle enzymes (ODC1, ARG1, OTC) and urea transporter UT-B. Mechanistically, brain urea accumulation likely stems from imbalanced urea cycle activity and impaired UT-B-mediated clearance, with compensatory UT-B upregulation specifically in the substantia nigra. In vitro, MPTP-treated neuronal cells showed increased enzyme and UT-B expression, while high urea directly suppressed tyrosine hydroxylase (TH). Importantly, ODC1 knockdown reversed urea dysmetabolism, restored TH, and alleviated neuronal damage. These findings establish ODC1-mediated urea cycle dysregulation as a core metabolic feature of PD, proposing ODC1 or urea metabolism as novel therapeutic targets. |
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| ISSN: | 2373-8057 |