Human NPCs can degrade α-syn fibrils and transfer them preferentially in a cell contact-dependent manner possibly through TNT-like structures
Human NPCs can degrade α-syn fibrils and transfer them preferentially in a cell contact-dependent manner possibly through TNT-like structures
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DOI：
10.1016/j.nbd.2019.104609
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发表时间：
2019-12-01
影响因子：
6.1
通讯作者：
Zurzolo, Chiara
中科院分区：
文献类型：
--
作者：
Grudina, Clara;Kouroupi, Georgia;Zurzolo, Chiara
帕金森病（PD）是第二常见的神经退行性疾病，中脑多巴胺能神经元的丧失导致运动功能障碍。将人诱导多能干细胞（iPSC）移植到受PD影响的患者的大脑中是已经获得兴趣以补偿神经元变性和改善疾病症状的治疗方法之一。然而，只有一部分移植的细胞可以分化为成熟的神经元，而大多数仍处于未分化状态。在这里，我们研究了源自iPSC的人神经元前体细胞（hNPC）是否在α-突触核蛋白（alpha-syn）病理学中发挥积极作用。我们的研究结果表明，α-syn纤维被hNPC吸收，并优先定位在溶酶体中，在那里它们可以被降解。然而，α-syn原纤维也以细胞与细胞接触依赖性方式在hNPC之间转移，并且在隧道纳米管（TNT）样结构中发现。因此，NPC在alpha-syn病理学的进展中可能具有双重作用，这在人类移植中应予以考虑。
Parkinson's disease (PD) is the second most common neurodegenerative disorder whereby loss of midbrain dopaminergic neurons results in motor dysfunction. Transplantation of human induced pluripotent stem cells (iPSCs) into the brain of patients affected by PD is one of the therapeutic approaches that has gained interest to compensate for the degeneration of neurons and improve disease symptoms. However, only a part of transplanted cells can differentiate into mature neurons while the majority remains in undifferentiated state. Here we investigated whether human neuronal precursor cells (hNPCs) derived from iPSCs have an active role in alpha-synuclein (alpha-syn) pathology. Our findings demonstrate that alpha-syn fibrils are taken up by hNPCs and are preferentially localized in lysosomes where they can be degraded. However, alpha-syn fibrils are also transferred between hNPCs in a cell-to-cell contact dependent manner, and are found in tunneling nanotube (TNT)-like structures. Thus, NPCs can have a dual role in the progression of alpha-syn pathology, which should be considered in human transplants.