Preclinical assessment of the therapeutic potential of dopamine (DA) neuron replacement in Parkinson’s disease (PD) has primarily been performed in the 6-hydroxydopamine toxin model. While this is a good model to assess graft function, it does not reflect the pathological features or progressive nature of the disease. In this study, we establish a humanized transplantation model of PD that better recapitulates the main disease features, obtained by coinjection of preformed human α-synuclein (α-syn) fibrils and adeno-associated virus (AAV) expressing human wild-type α-syn unilaterally into the rat substantia nigra (SN). This model gives rise to DA neuron dysfunction and progressive loss of DA neurons from the SN and terminals in the striatum, accompanied by extensive α-syn pathology and a prominent inflammatory response, making it an interesting and relevant model in which to examine long-term function and integrity of transplanted neurons in a PD-like brain. We transplanted DA neurons derived from human embryonic stem cells (hESCs) into the striatum and assessed their survival, growth, and function over 6 to 18 wk. We show that the transplanted cells, even in the presence of ongoing pathology, are capable of innervating the DA-depleted striatum. However, on closer examination of the grafts, we found evidence of α-syn pathology in the form of inclusions of phosphorylated α-syn in a small fraction of the grafted DA neurons, indicating host-to-graft transfer of α-syn pathology, a phenomenon that has previously been observed in PD patients receiving fetal tissue grafts but has not been possible to demonstrate and study in toxin-based animal models.

临床上对多巴胺（DA）神经元替代治疗帕金森氏病（PD）的治疗潜力的临床前评估主要是在6-羟基多巴胺毒素模型中进行的。虽然这是评估移植物功能的良好模型，但不能反映疾病的病理特征或进行性。在这项研究中，我们建立了PD的人源化移植模型，该模型可以更好地概括主要疾病特征，这是通过预先注射表达人野生型α-的人α-突触核蛋白（α-syn）原纤维和腺相关病毒（AAV）获得的。 syn单侧进入大鼠黑质（SN）。这种模型会引起DA神经元功能障碍和DA神经元从纹状体的SN和末端逐渐丧失，并伴有广泛的α-syn病理和明显的炎症反应，使其成为一种有趣且相关的模型，可用于检查PD样大脑中已移植神经元的长期功能和完整性。我们将源自人类胚胎干细胞（hESCs）的DA神经元移植到纹状体中，并评估了它们在6至18周内的存活，生长和功能。我们显示，即使在进行中的病理学存在下，移植的细胞也能够支配DA缺失的纹状体。然而，在对移植物进行仔细检查时，我们发现了α-syn病理学的证据，即在少量移植的DA神经元中以磷酸化的α-syn夹杂物的形式存在，表明了α-syn病理学从宿主到移植物的转移，这种现象先前已在接受胎儿组织移植的PD患者中观察到，但无法在基于毒素的动物模型中进行证实和研究。