Erk5-mediated microglial ferroptosis drives ischemic white matter damage via the Nfatc4–Clptm1l axis
Abstract
Ischemic white matter damage is a significant pathological feature of chronic cerebral hypoperfusion, leading to cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. In this study, we identify a causal association between genetically predicted extracellular signal-regulated kinase 5 (ERK5) expression and higher white matter hyperintensity volume through druggable target screening, suggesting its potential as a therapeutic target for white matter damage. Using different animal models of white matter damage, we show that Erk5 expression is significantly upregulated in microglia following both ischemic and demyelinating injury, correlating with the severity of white matter damage. Mechanistically, Erk5 exacerbates white matter damage by promoting microglial ferroptosis through the phosphorylation of nuclear factor of activated T-cells, cytoplasmic 4 (Nfatc4), which subsequently activates the expression of cleft lip and palate transmembrane protein 1-like protein (Clptm1l), a lipid scramblase involved in ferroptosis. Pharmacological and genetic inhibition of Erk5 in microglia effectively mitigates oxidative stress, lipid peroxidation, and ferroptosis, leading to a reduction in white matter damage and improved cognitive function. These findings underscore the potential of targeting the Erk5–Nfatc4–Clptm1l axis as a therapeutic strategy for ischemic white matter damage. Our study offers valuable insights into the molecular pathways driving white matter damage and provides a framework for the clinical translation of Erk5 inhibitors in the treatment of ischemic white matter damage.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Yun-Hui Chu
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Lu-Yang Zhang
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Jia-Yi He
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Ya-Fang Wang
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Ming-Hao Dong
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Yun-Fan You
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Xiao-Wei Pang
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Li-Fang Zhu
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Hang Zhang
Lu-Lu Xu
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Lian Chen
Luo-Qi Zhou
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Jun Xiao
Ke Shang
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Jian-Ke Gong
College of Life Science and Technology, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology
Wei Wang
Dai-Shi Tian
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Chuan Qin
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology