Tuddenham John F, Fujita Masashi, Lee Emily, Nimmagadda Nivedita, Khairallah Anthony, Harbison Claire, Flowers Xena E, Coronas-Samano Guillermo, Maniatis Silas, Daly Aidan, Schneider Julie A, Teich Andrew F, Vonsattel Jean Paul G, Sims Peter A, Elyaman Wassim, Bradshaw Elizabeth M, Ostrow Lyle W, Phatnani Hemali, Shneider Neil A, Bennett David A, De Jager Philip L, Przedborski Serge, Menon Vilas, Olah Marta
Department of Neurology, Divisions of Neuroimmunology/Translational Neurobiology/None, Columbia University Medical Center, New York, NY, USA.
Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Acta Neuropathol. 2025 Jul 29;150(1):10. doi: 10.1007/s00401-025-02913-3.
Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.
由于小胶质细胞参与肌萎缩侧索硬化症（ALS）的进展，开发针对ALS中特定小胶质细胞反应的治疗方法至关重要。我们的研究确定，人类ALS原发性运动皮层和脊髓中主要的小胶质细胞亚群是一种未分化的表型，其呼吸电子传递失调。此外，我们发现干扰素反应性小胶质细胞亚群在疾病进展迅速的供体中富集，而先前描述的一种潜在的保护性小胶质细胞表型在ALS中减少。此外，我们观察到在ALS中枢神经系统中，主要是脊髓中，非小胶质细胞免疫细胞（主要是NK/T细胞）富集。这些发现为开发小胶质细胞亚群特异性治疗干预措施以减缓甚至阻止ALS进展铺平了道路。
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