Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Translational Science Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Nat Commun. 2024 Mar 20;15(1):2497. doi: 10.1038/s41467-024-46695-w.
Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited evidence of lipid dysmetabolism, autophagy dysregulation and deficient phagocytosis, a canonical microglia function. Mutant PFN1 also displayed enhanced binding affinity for PI3P, a critical signaling molecule involved in autophagic and endocytic processing. Our cumulative data implicate a gain-of-toxic function for mutant PFN1 within the autophagic and endo-lysosomal pathways, as administration of rapamycin rescued phagocytic dysfunction in ALS-PFN1 iMGs. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and implicate microglial vesicular degradation pathways in the pathogenesis of these disorders.
小胶质细胞在神经退行性疾病发病机制中发挥着关键作用，但小胶质细胞功能障碍和毒性的机制仍有待阐明。为了研究与神经退行性疾病相关的基因对小胶质细胞固有特性的影响，我们研究了源自人类诱导多能干细胞（iPSC）的小胶质细胞样细胞（iMGs），这些细胞中存在肌动蛋白丝相关蛋白 1（PFN1）突变，可导致肌萎缩侧索硬化症（ALS）。携带 ALS 相关 PFN1 突变的 iMGs 表现出脂质代谢紊乱、自噬失调和吞噬作用缺陷的证据，这是小胶质细胞的一种典型功能。突变型 PFN1 还显示出与 PI3P 更强的结合亲和力，PI3P 是参与自噬和内吞作用的关键信号分子。我们的累积数据表明，突变型 PFN1 在自噬和内溶酶体途径中具有毒性作用的获得，因为雷帕霉素的给药可挽救 ALS-PFN1 iMGs 的吞噬功能障碍。这些结果表明 iMGs 可用于神经退行性疾病研究，并提示小胶质细胞囊泡降解途径参与这些疾病的发病机制。
