Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo.
Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo.
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DOI：
10.1371/journal.pone.0039465
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Brundin P
中科院分区：
文献类型：
--
作者：
Angot E;Steiner JA;Lema Tomé CM;Ekström P;Mattsson B;Björklund A;Brundin P
一些帕金森病患者已经接受了纹状体内移植胎儿多巴胺能神经元的治疗。尸检后，手术后10-22年，一些移植的神经元含有与宿主大脑中观察到的类似的路易体。许多研究试图在细胞和动物模型中解释这些发现。在细胞培养中，已经发现α-突触核蛋白通过包括外泌体转运和内吞作用的机制从一个细胞转移到另一个细胞，并且在某些情况下在受体细胞中种子聚集。在动物模型中，已显示α-突触核蛋白从宿主脑细胞转移到移植神经元，但报道的事件频率相对较低，并且对转移的α-突触核蛋白的潜在机制以及命运知之甚少。我们现在证明了α-突触核蛋白从一个过度表达人α-突触核蛋白的大鼠脑中频繁转移到移植的多巴胺能神经元中。此外，我们表明，该模型可用于探索α-突触核蛋白的细胞间转移的机制。因此，我们提供了证据，证明内吞作用参与体内α-突触核蛋白的摄取，并通过转移的α-突触核蛋白在受体神经元中接种内源性α-突触核蛋白的聚集。最后，我们表明，至少在所研究的细胞的一个子集，传递的α-突触核蛋白是敏感的蛋白酶K。我们的新模型系统可用于测试抑制α-突触核蛋白的细胞间转移的化合物，因此可能延缓帕金森神经病理学的进展。
Several people with Parkinson’s disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10–22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.
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影响因子：
4.8
作者：
Grimm, D
通讯作者：
Grimm, D
影响因子：
5.3
作者：
Barker, RA;Dunnett, SB;Fawcett, JW
通讯作者：
Fawcett, JW
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
4.8
作者：
Danzer, Karin M.;Ruf, Wolfgang P.;McLean, Pamela J.
通讯作者：
McLean, Pamela J.
DOI：
10.1016/0165-3806(86)90174-4
发表时间：
1986-01-01
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
BRUNDIN, P;ISACSON, O;BJORKLUND, A
通讯作者：
BJORKLUND, A