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

J Nutr. 2023 Jan;153(1):167-175. doi: 10.1016/j.tjnut.2022.11.006. Epub 2022 Dec 21.

Abstract

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 μg/g) or Zn deficient (ZnD; <5 μg/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 α-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.

Keywords: Parkinson disease; behavior; dopaminergic neuron; transcriptomics; zinc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / metabolism
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Diet
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism
  • Male
  • Malnutrition*
  • Mice
  • Mice, Inbred C57BL
  • Parkinson Disease* / metabolism
  • Substantia Nigra / metabolism
  • Zinc

Substances

  • Dopamine
  • Zinc
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine