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Peer-reviewedCC BYJournal of Neuroinflammation

SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis

  • Meijun He1
  • Chaoran Wu1
  • Mengqiu Hu1
  • Xiayi Shi1
  • Ruiqi Liu1
  • Yujie Tong1
  • Heng Wang1
  • Haoran Hu1
  • Hong Liao1
  1. 1New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University
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Abstract

Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1G93A mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, SGK1 knockout in SOD1G93A mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1G93A mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1G93A mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.

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Cite

BibTeXRIS
BibTeX
@article{he2026sgk1mediated,
  title = {{SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis}},
  author = {Meijun He and Chaoran Wu and Mengqiu Hu and Xiayi Shi and Ruiqi Liu and Yujie Tong and Heng Wang and Haoran Hu and Hong Liao},
  journal = {Journal of Neuroinflammation},
  year = {2026},
  month = jul,
  doi = {10.1186/s12974-026-03925-w},
  url = {https://doi.org/10.1186/s12974-026-03925-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis
AU  - Meijun He
AU  - Chaoran Wu
AU  - Mengqiu Hu
AU  - Xiayi Shi
AU  - Ruiqi Liu
AU  - Yujie Tong
AU  - Heng Wang
AU  - Haoran Hu
AU  - Hong Liao
PY  - 2026
DA  - 2026/07/01
JO  - Journal of Neuroinflammation
DO  - 10.1186/s12974-026-03925-w
UR  - https://doi.org/10.1186/s12974-026-03925-w
AB  - Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1G93A mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, SGK1 knockout in SOD1G93A mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1G93A mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1G93A mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.
SN  - 1742-2094
ER  -