2. Academic Validation
  3. Ganoderic acid A mitigates dopaminergic neuron ferroptosis via inhibiting NCOA4-mediated ferritinophagy in Parkinson's disease mice

Ganoderic acid A mitigates dopaminergic neuron ferroptosis via inhibiting NCOA4-mediated ferritinophagy in Parkinson's disease mice

  • J Ethnopharmacol. 2024 May 17:332:118363. doi: 10.1016/j.jep.2024.118363.
Qiang-Ming Li 1,  Shu-Zhen Wu 1,  Xue-Qiang Zha 1,  Dan-Dan Zang 2,  Feng-Yun Zhang 3,  Jian-Ping Luo 4
Affiliations

Affiliations

  • 1 School of Food and Biological Engineering, Key Laboratory for Agricultural Products Processing of Anhui Province, Hefei University of Technology, 230601, Hefei, People's Republic of China.
  • 2 Center of Scientific Research, Anhui Medical University, 230032, Hefei, People's Republic of China.
  • 3 School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, People's Republic of China. Electronic address: zhangfy_2016@163.com.
  • 4 School of Food and Biological Engineering, Key Laboratory for Agricultural Products Processing of Anhui Province, Hefei University of Technology, 230601, Hefei, People's Republic of China. Electronic address: jianpingluo@hfut.edu.cn.
PMID: 38763373 DOI: 10.1016/j.jep.2024.118363
Abstract

Ethnopharmacological relevance: Ganoderma lucidum, a renowned tonic traditional Chinese medicine, is widely recognized for the exceptional activity in soothing nerves and nourishing the brain. It has been extensively employed to alleviate various neurological disorders, notably Parkinson's disease (PD).

Aim of the study: To appraise the antiparkinsonian effect of GAA, the main bioactive constituent of G. lucidum, and clarify the molecular mechanism through the perspective of ferritinophagy-mediated dopaminergic neuron Ferroptosis.

Materials and methods: PD mouse and cell models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), respectively. Cell viability, behavioral tests and immunofluorescence analysis were performed to evaluate the neurotoxicity, motor dysfunction and dopaminergic loss, respectively. Biochemical assay kits were used to determine the levels of iron, lipid Reactive Oxygen Species (ROS), malondialdehyde (MDA), total ROS and glutathione (GSH). Western blot and immunofluorescence were applied to detect the expressions of nuclear receptor co-activator 4 (NCOA4), ferritin heavy chain 1 (FTH1), p62 and LC3B. Additionally, NCOA4-overexpressing Plasmid Vector was constructed to verify the inhibitory effect of GAA on the neurotoxicity and ferroptosis-related parameters in PD models.

Results: GAA significantly mitigated MPP+/MPTP-induced neurotoxicity, motor dysfunction and dopaminergic neuron loss (p＜0.01 or p＜0.05). In contrast to MPP+/MPTP treatment, GAA treatment decreased the levels of iron, MDA, lipid and total ROS, while increasing the GSH level. GAA also reduced the levels of NCOA4 and LC3B, and enhanced the expressions of FTH1 and p62 in PD models (p＜0.01 or p＜0.05). However, the protective effect of GAA against the neurotoxicity, NCOA4-mediated ferritinophagy and Ferroptosis in PD model was abolished by the overexpression of NCOA4 (p＜0.01).

Conclusion: GAA exerted a protective effect on PD, and this effect was achieved by suppressing dopaminergic neuron Ferroptosis through the inhibition of NCOA4-mediated ferritinophagy.

Keywords

Ferritinophagy; Ferroptosis; GAA; NCOA4; Parkinson's disease.

Figures
Products