Zinc Deficiency Exacerbates Behavioral Impediments and Dopaminergic Neuron Degeneration in a Mouse Model of Parkinson Disease

Background: Circulating zinc (Zn) concentrations are lower than normal in patients with Parkinson disease (PD). It is unknown whether Zn deficiency increases the susceptibility to PD. Objectives: The study aimed to investigate the effect of dietary Zn deficiency on behaviors and dopaminergic neurons in a mouse model of PD and to explore potential mechanisms. Methods: Male C57BL/6J mice aged 8-10 wk were fed Zn adequate (ZnA; 30 mu g/g) or Zn deficient (ZnD; <5 mu g/g) diet throughout the experiments. Six weeks later 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was injected to generate the PD model. Controls were injected with saline. Thus, 4 groups (Saline-ZnA, Saline-ZnD, MPTP-ZnA, and MPTP-ZnD) were formed. The experiment lasted 13 wk. Open field test, rotarod test, immunohistochemistry, and RNA sequencing were performed. Data were analyzed with t-test, 2-factor ANOVA, or Kruskal-Wallis test. Results: Both MPTP and ZnD diet treatments led to a significant reduction in blood Zn concentrations (PMPTP = 0.012, PZn = 0.014), reduced total distance traveled (PMPTP < 0.001, PZn = 0.031), and affected the degeneration of dopaminergic neurons in the substantia nigra (PMPTP < 0.001, PZn = 0.020). In the MPTP-treated mice, the ZnD diet significantly reduced total distance traveled by 22.4% (P = 0.026), decreased latency to fall by 49.9% (P = 0.026), and reduced dopaminergic neurons by 59.3% (P = 0.002) compared with the ZnA diet. RNA sequencing analysis revealed a total of 301 differentially expressed genes (156 upregulated; 145 downregulated) in the substantia nigra of ZnD mice compared with ZnA mice. The genes were involved in a number of processes, including protein degradation, mitochondria integrity, and alpha-synuclein aggregation. Conclusions: Zn deficiency aggravates movement disorders in PD mice. Our results support previous clinical observations and suggest that appropriate Zn supplementation may be beneficial for PD.