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Dysregulated N6-methyladenosine modification in peripheral immune cells contributes to the pathogenesis of amyotrophic lateral sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurogenerative disorder with uncertain origins. Emerging evidence implicates N6-methyladenosine (m6A) modification in ALS pathogenesis. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and liquid chromatography–mass spectrometry were utilized for m6A profiling in peripheral immune cells and serum proteome analysis, respectively, in patients with ALS (n = 16) and controls (n = 6). The single-cell transcriptomic dataset (GSE174332) of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes. Analysis of peripheral immune cells revealed extensive RNA hypermethylation, highlighting candidate genes with differential m6A modification and expression, including C-X3-C motif chemokine receptor 1 (CX3CR1). In RAW264.7 macrophages, disrupted CX3CR1 signaling affected chemotaxis, potentially influencing immune cell migration in ALS. Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS. Cell type-specific expression variations of these genes in the central nervous system (CNS), particularly microglia, were observed. Intercellular communication between neurons and glial cells was selectively altered in ALS CNS. This integrated approach underscores m6A dysregulation in immune cells as a potential ALS contributor.

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Acknowledgements

We acknowledge the technical support received from our collaborators. The LC-MS and PRM were performed at Beijing Bioms Technology Co. Ltd. MeRIP-seq and MeRIP-qPCR were performed at Tianhao Co. Ltd. We would like to thank all patients and their families in participating and supporting this study. We also thank Dr. Boxuan Zhao for constructive discussion. We are obliged to Pineda et al. for making their human primary motor cortex scRNA-seq data publicly available.

This work was supported by the Strategic Priority Research Program (Pilot study) “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (No. XDB39040000), CAMS Innovation Fund for Medical Sciences (Nos. 2021-I2M-1-003 and 2021-I2M-1-034), National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-B-017), Beijing Natural Science Foundation (No. 7202158), National Natural Science Foundation of China (No. 81971293).

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  1. These authors contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Neurology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China

    Di He, Xunzhe Yang, Dongchao Shen, Qing Liu, Mingsheng Liu & Liying Cui

  2. Medical Doctor Program, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China

    Liyang Liu

  3. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100730, China

    Liyang Liu & Xue Zhang

  4. Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China

    Xue Zhang

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  2. Xunzhe Yang
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  3. Liyang Liu
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  4. Dongchao Shen
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  5. Qing Liu
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  6. Mingsheng Liu
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  7. Xue Zhang
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  8. Liying Cui
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Corresponding authors

Correspondence to Xue Zhang or Liying Cui.

Ethics declarations

Conflicts of interest Di He, Xunzhe Yang, Liyang Liu, Dongchao Shen, Qing Liu, Mingsheng Liu, Xue Zhang, and Liying Cui declare that they have no conflict of interest to be disclosed. The funding party is not involved in any aspect pertinent to the study, and none of the authors is financially related to pharmaceutical company or other agency.

The study was approved by the PUMCH Research Ethical Boards (Ethical Approval No. JS-2624) and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

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He, D., Yang, X., Liu, L. et al. Dysregulated N6-methyladenosine modification in peripheral immune cells contributes to the pathogenesis of amyotrophic lateral sclerosis. Front. Med. (2024). https://doi.org/10.1007/s11684-023-1035-5

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  • DOI: https://doi.org/10.1007/s11684-023-1035-5

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