近日，美国圣路易斯的华盛顿大学教授Marco Colonna及其课题组提出了人CSF1R基因突变影响小胶质细胞对脑白质完整性的维持。相关论文于2025年6月26日发表于国际顶尖学术期刊《自然—免疫学》杂志上。

小胶质细胞是大脑中的巨噬细胞，其发育和维持依赖于白细胞介素-34和集落刺激因子1 (CSF1)，并参与CSF1受体（CSF1R）。成人发病的脑白质病伴轴突球体和色素胶质（ALSP）是一种影响脑白质的神经退行性疾病，由CSF1R基因的杂合致病性突变引起。本研究探讨了死后脑标本ALSP主题化单核RNA测序的分子机制。结果显示ALSP脑中的小胶质细胞显著减少，剩余的细胞表现出独特的激活特征。

这种减少与髓鞘少突胶质细胞（OLs）的减少和neuropilin-2⁺ OLs的增加相关，具有应激反应和抗凋亡特征，由STAT3和成纤维细胞生长因子受体途径驱动。此外，星形胶质细胞表现出不适应激活和应激反应。这些发现强调了小胶质细胞在支持OL髓鞘形成和限制星形胶质细胞修复反应中的关键作用，提示了平衡CSF1R、成纤维细胞生长因子受体和STAT3通路的治疗策略，用于ALSP和其他遗传导管小胶质病。

附：英文原文

Title: Mutations in the human CSF1R gene impact microglia’s maintenance of brain white matter integrity

Author: Du, Siling, Zhou, Yingyue, Li, Dian, Lier, Julia, Cella, Marina, Tada, Mari, Hamasaki, Hideomi, Wu, Junjie, Cai, Zhangying, Orthmann-Murphy, Jennifer L., Kakita, Akiyoshi, Kipnis, Jonathan, Bergner, Caroline G., Colonna, Marco

Issue&Volume: 2025-06-26

Abstract: Microglia, the brain’s resident macrophages, depend on interleukin-34 and colony-stimulating factor 1 (CSF1) for their development and maintenance, engaging the CSF1 receptor (CSF1R). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disorder affecting the brain’s white matter, is caused by heterozygous pathogenic mutations in the CSF1R gene. This study investigated molecular mechanisms underlying ALSP using single-nucleus RNA sequencing on postmortem brain specimens. Results showed a significant reduction in microglia in ALSP brains, with remaining cells exhibiting a unique activation signature. This reduction correlated with decreased myelinating oligodendrocytes (OLs) and increased neuropilin-2+ OLs with a stress-response and anti-apoptotic signature, driven by STAT3 and fibroblast growth factor receptor pathways. Additionally, astrocytes displayed maladaptive activation and stress responses. These findings underscore microglia’s crucial role in supporting OL myelination and limiting astrocyte repair responses, suggesting therapeutic strategies balancing CSF1R, fibroblast growth factor receptor and STAT3 pathways for ALSP and other genetically caused microgliopathies.

DOI: 10.1038/s41590-025-02195-7

Source: https://www.nature.com/articles/s41590-025-02195-7