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Background <p>α-Synuclein oligomers (α-synOs) contribute to the initiation and progression of Parkinson’s disease (PD) by promoting neuronal death and activating glial cells. Clearing α-synOs while maintaining tissue homeostasis is a promising therapeutic strategy for PD.</p> Methods <p>We genetically engineered astrocytes with an anti-α-synO chimeric antigen receptor (CAR) consisting of a single-chain variable fragment targeting α-synOs and a truncated MerTK receptor, to direct their phagocytic activity against α-synOs.</p> Results <p>CAR-engineered astrocytes (CAR-A) showed significantly enhanced phagocytosis of α-synOs due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased the release of pro-inflammatory cytokines by inhibiting the NF-κB and cytokine receptor signaling pathways. Consistently, in situ CAR-A significantly ameliorated the motor and cognitive deficits of A53T mice by clearing α-synOs, creating a non-inflammatory microenvironment and restoring the viability of dopaminergic neurons.</p> Conclusions <p>CAR-A-based strategy is an effective treatment for PD-like mouse model. This in situ CAR-A technology provides an innovative and feasible strategy to treat PD and other brain disorders.</p>

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Attenuating α-synuclein pathology in mice with in situ engineered astrocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月20日

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  • Xiao-yu Du,
  • Jing Zhou,
  • Jie Zhu,
  • Lun Zhang,
  • Shuai Lu,
  • Shi-yu Liang,
  • Fang Cui,
  • Hao-han Zhang,
  • Fei Chen,
  • Ming-yue Jiao,
  • Ya-ru Huang,
  • Xiao-lin Yu,
  • Rui-tian Liu

摘要

Background

α-Synuclein oligomers (α-synOs) contribute to the initiation and progression of Parkinson’s disease (PD) by promoting neuronal death and activating glial cells. Clearing α-synOs while maintaining tissue homeostasis is a promising therapeutic strategy for PD.

Methods

We genetically engineered astrocytes with an anti-α-synO chimeric antigen receptor (CAR) consisting of a single-chain variable fragment targeting α-synOs and a truncated MerTK receptor, to direct their phagocytic activity against α-synOs.

Results

CAR-engineered astrocytes (CAR-A) showed significantly enhanced phagocytosis of α-synOs due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased the release of pro-inflammatory cytokines by inhibiting the NF-κB and cytokine receptor signaling pathways. Consistently, in situ CAR-A significantly ameliorated the motor and cognitive deficits of A53T mice by clearing α-synOs, creating a non-inflammatory microenvironment and restoring the viability of dopaminergic neurons.

Conclusions

CAR-A-based strategy is an effective treatment for PD-like mouse model. This in situ CAR-A technology provides an innovative and feasible strategy to treat PD and other brain disorders.