Deletion of ZNRF2 Exacerbates MPTP-Induced Parkinson's Disease by Activating mTOR-Mediated Neuroinflammatory Pathways

Parkinson's disease (PD) imposes a significant health burden among older adults and may be related to zinc and ring finger 2 (ZNRF2)-a member of the ubiquitination family. To investigate the role and mechanism of action of ZNRF2 in the regulation of mammalian target of rapamycin (mTOR)-mediated neuroinflammation in a mouse model of PD. Healthy mice were injected intraperitoneally with either saline (control) or MPTP 30 mg/kg. Mouse behavior was tested using rotarod and open field tests. The distribution and expression of tyrosine hydroxylase (TH) were determined by immunoblotting and immunohistochemistry. Inflammatory factors were evaluated using immunoblotting, enzyme-linked immunosorbent assay, and immunofluorescence assay. Compared with mice injected with saline, MPTP-treated mice showed significantly impaired locomotor activity, a significant decrease in the number of TH neurons, and a markedly altered morphology. ZNRF2 expression was significantly increased in the mesencephalon of MPTP-treated mice compared to that in control mice. ZNRF2 knockdown exacerbated motor dysfunction, accelerated dopamine neuron degeneration and death, increased the levels of pro-inflammatory factors (e.g., interleukin (IL)-1β, IL-6), and suppressed the expression of anti-inflammatory factors (e.g., IL-4, IL-10) in the central nervous system of MPTP-treated mice, with more pronounced activation of microglia and astrocytes. ZNRF2 knockdown significantly elevated phosphorylated mTOR protein levels after MPTP treatment; subsequently, phosphorylated mTOR protein levels were inhibited; dyskinesia and dopamine neuronal damage were significantly ameliorated, and neuroinflammation was suppressed in PD mice. ZNRF2 regulates the pathogenesis of MPTP-induced PD in mice via mechanisms related to mTOR-mediated neuroinflammation.