2. Academic Validation
  3. NRF2 activation suppresses motor neuron ferroptosis induced by the SOD1G93A mutation and exerts neuroprotection in amyotrophic lateral sclerosis

NRF2 activation suppresses motor neuron ferroptosis induced by the SOD1G93A mutation and exerts neuroprotection in amyotrophic lateral sclerosis

  • Neurobiol Dis. 2023 Jun 21;106210. doi: 10.1016/j.nbd.2023.106210.
Biying Yang 1,  Jingrui Pan 2,  Xiao-Ni Zhang 3,  Hongxuan Wang 3,  Lei He 3,  Xiaoming Rong 3,  Xiangpen Li 4,  Ying Peng 5
Affiliations

Affiliations

  • 1 Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 2 Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shantou, China.
  • 3 Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4 Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shantou, China. Electronic address: lixiangp@mail.sysu.edu.cn.
  • 5 Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: pengy2@mail.sysu.edu.cn.
PMID: 37352984 DOI: 10.1016/j.nbd.2023.106210
Abstract

The progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) is caused by a decline in motor neuron function, resulting in worsened motor impairments, malnutrition, respiratory failure and mortality, and there is a lack of effective clinical treatments. The exact mechanism of motor neuronal degeneration remains unclear. Previously, we reported that Ferroptosis, which is characterized by the accumulation of lipid peroxide and glutathione depletion in an iron-dependent manner, contributed to motor neuronal death in ALS cell models with the hSOD1G93A (human Cu/Zn-superoxide dismutase) gene mutation. In this study, we further explored the role of Ferroptosis in motor neurons and its regulation in mutant hSOD1G93A cell and mouse models. Our results showed that Ferroptosis was activated in hSOD1G93A NSC-34 cells and mouse models, which was accompanied by decreased nuclear retention of nuclear factor erythroid 2-related factor 2 (NRF2) and downregulation of solute carrier family 7 member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) levels. Moreover, RTA-408, an NRF2 activator, inhibited Ferroptosis in hSOD1G93A NSC-34 cells by upregulating the protein expression of SLC7A11 and GPX4. Moreover, hSOD1G93A mice treated with RTA-408 showed obvious improvements in body weight and motor function. Our study demonstrated that Ferroptosis contributed to the toxicity of motor neurons and that activating NRF2 could alleviate neuronal degeneration in ALS with the hSOD1G93A mutation.

Keywords

Amyotrophic lateral sclerosis; Ferroptosis; NRF2; Omavleoxolone RTA408; SOD1(G93A).

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