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<p>Parkinson’s disease (PD) is characterized by the progressive degeneration of midbrain dopaminergic (DA) neurons, leading to disruption of the nigrostriatal pathway and motor deficits. Here, we present an optimized protocol for generating human midbrain organoids (hMOs) suitable for homotopic transplantation, through sequential modifications. Homotopic transplantation of these optimized hMOs into the substantia nigra (SN) of 6-hydroxydopamine (6-OHDA)-lesioned PD mice resulted in significant graft survival, with a majority of grafted cells expressing the A9-specific neuronal marker GIRK2. The grafts reconstituted the nigrostriatal pathway, as confirmed by restored DA fiber density, elevated striatal dopamine levels, and retrograde AAV tracing. These structural improvements were accompanied by notable behavioral recovery, including reduced apomorphine-induced rotations, enhanced rotarod performance, and restored limb symmetry in cylinder tests. Our findings demonstrate that optimized hMOs, when transplanted into their native niche, can reestablish functional circuitry and alleviate motor deficits, providing an efficient and clinically relevant strategy for PD therapy.</p>

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Optimized Midbrain Organoid Transplantation Restores Dopaminergic Nigrostriatal Pathway and Motor Function in Parkinson’s Disease Mouse Model

  • 期刊论文

  • 发表日期：

    2026年7月6日

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  • Lin-Bo Chen,
  • Xin-Yu She,
  • Xi Jiang,
  • Peng-Jian Wu,
  • Chang-Qing Zheng,
  • Jun Yao

摘要

Parkinson’s disease (PD) is characterized by the progressive degeneration of midbrain dopaminergic (DA) neurons, leading to disruption of the nigrostriatal pathway and motor deficits. Here, we present an optimized protocol for generating human midbrain organoids (hMOs) suitable for homotopic transplantation, through sequential modifications. Homotopic transplantation of these optimized hMOs into the substantia nigra (SN) of 6-hydroxydopamine (6-OHDA)-lesioned PD mice resulted in significant graft survival, with a majority of grafted cells expressing the A9-specific neuronal marker GIRK2. The grafts reconstituted the nigrostriatal pathway, as confirmed by restored DA fiber density, elevated striatal dopamine levels, and retrograde AAV tracing. These structural improvements were accompanied by notable behavioral recovery, including reduced apomorphine-induced rotations, enhanced rotarod performance, and restored limb symmetry in cylinder tests. Our findings demonstrate that optimized hMOs, when transplanted into their native niche, can reestablish functional circuitry and alleviate motor deficits, providing an efficient and clinically relevant strategy for PD therapy.