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

  • Transl Neurodegener. 2025 Nov 20;14(1):58. doi: 10.1186/s40035-025-00518-0.
Xiao-Yu Du  #  1  2 ,  Jing Zhou  #  3 ,  Jie Zhu  #  1  2 ,  Lun Zhang  1  2 ,  Shuai Lu  1 ,  Shi-Yu Liang  1  2 ,  Fang Cui  1  2 ,  Hao-Han Zhang  1 ,  Fei Chen  1  4 ,  Ming-Yue Jiao  1 ,  Ya-Ru Huang  5 ,  Xiao-Lin Yu  6 ,  Rui-Tian Liu  7
Affiliations
  • 1. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China.
  • 2. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3. Department of Geriatric Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, 100144, China.
  • 4. Ningxia University, Yinchuan, 750021, China.
  • 5. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China. [email protected].
  • 6. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China. [email protected].
  • 7. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China. [email protected].
  • # Contributed equally.
PMID: 41261395 DOI: 10.1186/s40035-025-00518-0
Abstract

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.

Keywords
Astrocyte; Chimeric antigen receptor; Parkinson’s disease; α-Synuclein oligomer.
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