C9orf72六核苷酸重复扩增损害ALS的小胶质细胞反应，这一成果由比利时鲁汶大学Philip Van Damme研究小组经过不懈努力而取得。2025年10月14日出版的《自然—神经科学》发表了这项成果。

该课题组从散发性ALS（sALS）和C9orf72型ALS（C9-ALS）患者的脊髓和运动皮质中生成了单核转录组。

本研究证实了C9orf72在小胶质细胞中高表达，并观察到六核苷酸重复扩增（HRE）导致单倍不全。当sALS小胶质细胞向疾病相关的细胞状态过渡时，C9orf72 HRE小胶质细胞表现出减少的反应，内溶酶体途径发生改变。研究人员在人类小胶质细胞异种移植模型中证实了这些观察结果，其中C9orf72突变导致激活降低。该团队还证实了C9orf72 HRE和C9orf72缺陷诱导多能干细胞（iPSC）衍生的小胶质细胞的内溶酶体改变。小组还发现C9orf72 HRE星形胶质细胞的反应减弱，并提供了失调配体小胶质细胞和星形胶质细胞中的受体对。他们的数据强调了散发性和遗传性ALS的细胞底物的变化，这对患者分层和选择适当的治疗方法具有重要意义。

研究人员表示，小胶质细胞和神经炎症与肌萎缩侧索硬化症（ALS）有关，但确切的潜在分子机制尚不清楚。

附：英文原文

Title: C9orf72 hexanucleotide repeat expansions impair microglial response in ALS

Author: Masrori, Pegah, Bijnens, Baukje, Fumagalli, Laura, Davie, Kristofer, Poovathingal, Suresh Kumar, Meese, Tim, Storm, Annet, Hersmus, Nicole, Fazal, Raheem, van den Biggelaar, Diede, Asselbergh, Bob, Gruel, Roxane, Van Den Daele, Johanna, Denton, Heidi, Miquel, Paula Polanco, Manzella, Simona, De Vos, Winnok H., Chandran, Siddhartan, Van Den Bosch, Ludo, Thal, Dietmar Rudolf, Mancuso, Renzo, Van Damme, Philip

Issue&Volume: 2025-10-14

Abstract: Microglia and neuroinflammation are involved in amyotrophic lateral sclerosis (ALS), but the precise underlying molecular mechanisms remain elusive. We generated single-nuclei transcriptomes from the spinal cord and motor cortex of patients with sporadic ALS (sALS) and C9orf72 ALS (C9-ALS). Here we confirmed that C9orf72 is highly expressed in microglia and observed that the hexanucleotide repeat expansion (HRE) results in haploinsufficiency. Whereas sALS microglia transitioned toward disease-associated cell states, C9orf72 HRE microglia exhibited a diminished response, with alterations in endolysosomal pathways. We confirmed these observations using a human microglia xenograft model, in which C9orf72 mutations led to a reduced activation. We also confirmed the endolysosomal alterations in C9orf72 HRE and C9orf72-deficient induced pluripotent stem cell (iPSC)-derived microglia. We also found a diminished response of C9orf72 HRE astrocytes and provided a map of dysregulated ligandreceptor pairs in microglia and astrocytes. Our data highlight variations in the cellular substrate of sporadic and inherited forms of ALS, which have implications for patient stratification and selection of appropriate treatments.

DOI: 10.1038/s41593-025-02075-1

Source: https://www.nature.com/articles/s41593-025-02075-1