PMID- 37352984
OWN - NLM
STAT- MEDLINE
DCOM- 20230808
LR  - 20230808
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 184
DP  - 2023 Aug
TI  - NRF2 activation suppresses motor neuron ferroptosis induced by the SOD1(G93A) 
      mutation and exerts neuroprotection in amyotrophic lateral sclerosis.
PG  - 106210
LID - S0969-9961(23)00225-5 [pii]
LID - 10.1016/j.nbd.2023.106210 [doi]
AB  - 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 hSOD1(G93A) (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 hSOD1(G93A) cell and mouse models. Our results showed that 
      ferroptosis was activated in hSOD1(G93A) 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 hSOD1(G93A) NSC-34 cells by upregulating the protein 
      expression of SLC7A11 and GPX4. Moreover, hSOD1(G93A) 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 
      hSOD1(G93A) mutation.
CI  - Copyright (c) 2023. Published by Elsevier Inc.
FAU - Yang, Biying
AU  - Yang B
AD  - 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.
FAU - Pan, Jingrui
AU  - Pan J
AD  - 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, Shanwei, China.
FAU - Zhang, Xiao-Ni
AU  - Zhang XN
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 
      Guangzhou, China.
FAU - Wang, Hongxuan
AU  - Wang H
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 
      Guangzhou, China.
FAU - He, Lei
AU  - He L
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 
      Guangzhou, China.
FAU - Rong, Xiaoming
AU  - Rong X
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 
      Guangzhou, China.
FAU - Li, Xiangpen
AU  - Li X
AD  - 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, Shanwei, China. Electronic address: 
      lixiangp@mail.sysu.edu.cn.
FAU - Peng, Ying
AU  - Peng Y
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230621
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (NF-E2-Related Factor 2)
RN  - G69Z98951Q (omaveloxolone)
RN  - 0 (SOD1 protein, human)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.15.1.1 (Superoxide Dismutase-1)
RN  - 0 (NFE2L2 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Amyotrophic Lateral Sclerosis/metabolism
MH  - Disease Models, Animal
MH  - *Ferroptosis
MH  - Mice, Transgenic
MH  - Motor Neurons/metabolism
MH  - Mutation/genetics
MH  - *Neurodegenerative Diseases/metabolism
MH  - Neuroprotection
MH  - NF-E2-Related Factor 2/metabolism
MH  - Superoxide Dismutase/genetics
MH  - Superoxide Dismutase-1/genetics/metabolism
OTO - NOTNLM
OT  - Amyotrophic lateral sclerosis
OT  - Ferroptosis
OT  - NRF2
OT  - Omavleoxolone RTA408
OT  - SOD1(G93A)
COIS- Declaration of Competing Interest The authors declare no conflict of interest.
EDAT- 2023/06/24 11:42
MHDA- 2023/08/07 06:41
CRDT- 2023/06/23 19:13
PHST- 2023/04/06 00:00 [received]
PHST- 2023/05/27 00:00 [revised]
PHST- 2023/06/20 00:00 [accepted]
PHST- 2023/08/07 06:41 [medline]
PHST- 2023/06/24 11:42 [pubmed]
PHST- 2023/06/23 19:13 [entrez]
AID - S0969-9961(23)00225-5 [pii]
AID - 10.1016/j.nbd.2023.106210 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2023 Aug;184:106210. doi: 10.1016/j.nbd.2023.106210. Epub 2023 Jun 
      21.