Glymphatic Dysfunction Drives High‐Urea‐Induced Neurodegeneration in Parkinson's Disease

BACKGROUND: Disruption of brain urea homeostasis has been implicated in neurodegenerative disorders, yet its molecular mechanisms remain elusive. This study aimed to investigate how urea metabolic disturbance drives neurodegeneration through astrocytic polarity impairment and to identify potential therapeutic targets. METHODS: A high-urea mouse model was generated by urea transporter B (UT-B) knockout. Pharmacological inhibition and genetic intervention were applied to examine dipeptidyl peptidase-like protein 6 (DPP6), protein kinase C eta (PKCη), and aquaporin-4 (AQP4) expression and localization in astrocytes. Glymphatic clearance, α-synuclein (α-syn) pathology propagation, and dopaminergic neurodegeneration were evaluated. RESULTS: Urea upregulated astrocytic DPP6, activated PKCη signaling, and induced AQP4 endocytosis with loss of membrane polarity, leading to impaired glymphatic clearance, accelerated α-syn spread, and dopaminergic neuronal degeneration. Mechanistically, the DPP6-PKCη axis directly regulated AQP4 membrane localization; inhibiting this pathway pharmacologically or genetically rescued all pathological phenotypes. CONCLUSIONS: This study reveals that urea metabolic disruption promotes neurodegenerative progression via the DPP6-PKCη-AQP4 pathway by compromising astrocytic polarity, offering new therapeutic targets for Parkinson's disease. © 2026 International Parkinson and Movement Disorder Society.