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A Cross-Organ Single-Cell Atlas of ALS Reveals Tissue-Specific Remodeling, and Druggable Biomarkers

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作者

    Jianyu Pang， 
    Jianyu Pang
    • School of Medicine, The Chinese University of Hong Kong, Shenzhen, China
    • The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Centre, Shenzhen
    Mingye Wang， 
    Mingye Wang
    • School of Medicine, The Chinese University of Hong Kong, Shenzhen, China
    • The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Centre, Shenzhen
    Jiahao Chen， 
    Jiahao Chen
    • School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
    • Institute of Traditional Chinese Medicine Model Organisms, Guangzhou University of Chinese Medicine, Guangzhou, China
    Yining Liu， 
    Yining Liu
    Jing Zhang， 
    Jing Zhang
    • The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Centre, Shenzhen, China
    Hao Zhang， 
    Hao Zhang
    Lei Gao， 
    Lei Gao
    • School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
    • Institute of Traditional Chinese Medicine Model Organisms, Guangzhou University of Chinese Medicine, Guangzhou, China
    Chong Gao， 
    Chong Gao
    • School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
    Limin Xu
    Limin Xu
    • School of Medicine, The Chinese University of Hong Kong, Shenzhen, China
分类
计算生物学与生物信息学
关键词
Amyotrophic lateral sclerosis; Single-nucleus RNA sequencing; Cross-tissue atlas; Biomarkers; Potential therapeutic compounds

摘要

Background: Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous neurodegenerative disorder. Its pathological process involves not only motor neuron degeneration but also glial abnormalities, disrupted intercellular communication, and remodeling of peripheral tissues such as skeletal muscle. However, the cross-tissue pathological features of ALS across the brain, spinal cord, and skeletal muscle, as well as their molecular basis, remain insufficiently characterized.

Methods: In this study, we integrated single-nucleus RNA sequencing (snRNA-seq) data from the brain, spinal cord, and skeletal muscle of SOD1, TDP43, and wild-type mice to construct a cross-tissue cellular atlas. Based on stringent quality control, we performed cell type annotation, proportion analysis, irGSEA functional scoring, CellChat-based intercellular communication inference, pseudotime trajectory analysis, pySCENIC-based transcriptional regulatory network reconstruction, and multi-model machine learning screening. Subsequently, DeepPurpose and AutoDock were used to perform drug-target prediction and molecular docking analyses for candidate biomarkers.

Results: A total of 109,875 high-quality cells were obtained, and 18 cell types were identified. The results showed that different ALS genotypes induced pronounced and tissue-specific remodeling of cellular composition and functional states in the brain, spinal cord, and skeletal muscle. Functional scoring revealed marked tissue-dependent differences in neuroinflammation, oxidative metabolism, proteostasis imbalance, and aberrant cell proliferation. Cell communication analysis indicated that NRXN, NEGR, NRG, and PTPRM signaling pathways play central roles in different tissues, suggesting remodeling of synaptic maintenance and cell adhesion networks in ALS. Pseudotime analysis further demonstrated distinct temporal reprogramming patterns in neuronal and stromal cell differentiation trajectories between the SOD1 and TDP43 models. After integrating multidimensional features, machine learning identified four high-confidence biomarkers: Tac2, Gsn, Taco1, and Sod1. Drug screening and molecular docking further revealed potential high-affinity interactions between sulforaphane, phenylhydrazine, and several candidate compounds with key targets.

Conclusion: This study systematically reveals the pathological heterogeneity of ALS across tissues, cell types, and molecular layers, elucidates its core intercellular communication networks and key candidate biomarkers, and provides a potential molecular foundation and candidate drug leads for targeted intervention and precision therapy in ALS.

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DOI：

https://doi.org/10.65215/LTSpreprints.2026.04.28.000208

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208

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2026-04-28

如何引用

Pang, J., Wang, M., Chen, J., Liu, Y., Zhang, J., Zhang, H., Gao, L., Gao, C., & Xu, L. (2026). A Cross-Organ Single-Cell Atlas of ALS Reveals Tissue-Specific Remodeling, and Druggable Biomarkers. 浪淘沙预印本平台. https://doi.org/10.65215/LTSpreprints.2026.04.28.000208

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