Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD
Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD
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DOI：
10.1073/pnas.2001305117
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发表时间：
2020-06-30
影响因子：
11.1
通讯作者：
Parmar, Malin
中科院分区：
文献类型：
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作者：
Hoban, Deirdre B.;Shrigley, Shelby;Parmar, Malin
多巴胺（DA）神经元替代治疗帕金森病（PD）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，但它不能反映疾病的病理特征或进展性质。在这项研究中，我们建立了一个人源化的PD移植模型，更好地概括了主要的疾病特征，通过共注射预先形成的人α-突触核蛋白（α-syn）纤维和腺相关病毒（AAV）表达人类野生型α-syn单侧进入大鼠黑质（SN）。该模型引起DA神经元功能障碍和DA神经元从SN和纹状体中的终末的进行性损失，伴随着广泛的α-syn病理学和显著的炎症反应，使其成为一个有趣的和相关的模型，其中检查PD样脑中移植神经元的长期功能和完整性。我们将来自人胚胎干细胞（hESC）的DA神经元移植到纹状体中，并在6至18周内评估其存活、生长和功能。我们表明，移植的细胞，即使在正在进行的病理学的存在下，是能够支配DA耗尽纹状体。然而，在对移植物进行更仔细的检查时，我们发现了在一小部分移植的DA神经元中包含磷酸化α-syn的形式的α-syn病理学的证据，表明α-syn病理学的宿主-移植物转移，这是先前在接受胎儿组织移植物的PD患者中观察到的现象，但不可能在基于毒素的动物模型中证明和研究。
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 alpha-synuclein (alpha-syn) fibrils and adeno-associated virus (AAV) expressing human wild-type alpha-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 alpha-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 alpha-syn pathology in the form of inclusions of phosphorylated alpha-syn in a small fraction of the grafted DA neurons, indicating host-to-graft transfer of alpha-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.