Exosome secretion is a key pathway for clearance of pathological TDP-43
Exosome secretion is a key pathway for clearance of pathological TDP-43
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DOI：
10.1093/brain/aww237
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发表时间：
2016-12-01
期刊：
影响因子：
14.5
通讯作者：
Julien, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Iguchi, Yohei;Eid, Lara;Julien, Jean-Pierre
胞浆TDP-43聚集是肌萎缩侧索硬化和额颞叶变性的病理标志。在这里，我们研究了外泌体在TDP-43聚集体的分泌和繁殖中的作用。在Neuro 2a细胞和原代神经元分泌的外泌体中检测到TDP-43，但在星形胶质细胞或小胶质细胞中未检测到TDP-43。有证据表明，蛋白质聚集和自噬抑制是促进外泌体分泌TDP-43的因素。我们还报告了外泌体TDP-43全长和C-末端片段种类的水平在人类肌萎缩侧索硬化症脑中上调。将Neuro 2a细胞暴露于来自肌萎缩侧索硬化脑的外泌体，而不是来自对照脑的外泌体，引起TDP-43的细胞质重新分布，表明分泌的外泌体可能有助于TDP-43蛋白质病的传播。然而，通过用GW 4869灭活中性鞘磷脂酶2或通过沉默RAB 27 A来抑制外泌体分泌引起Neuro 2a细胞中TDP-43聚集体的形成。此外，GW 4869的施用加重了表达人TDP-43（A315 T）突变体的转基因小鼠的疾病表型。因此，即使结果表明含有病理性TDP-43的外泌体可能在TDP-43蛋白质病的传播中起关键作用，基于抑制外泌体产生的肌萎缩侧索硬化症的治疗策略似乎是不合适的，因为体内数据表明外泌体分泌在病理性TDP-43的神经元清除中起总体有益的作用。
Cytoplasmic TDP-43 aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here we investigated the role of exosomes in the secretion and propagation of TDP-43 aggregates. TDP-43 was detected in secreted exosomes from Neuro2a cells and primary neurons but not from astrocytes or microglia. Evidence is presented that protein aggregation and autophagy inhibition are factors that promote exosomal secretion of TDP-43. We also report that levels of exosomal TDP-43 full length and C-terminal fragment species are upregulated in human amyotrophic lateral sclerosis brains. Exposure of Neuro2a cells to exosomes from amyotrophic lateral sclerosis brain, but not from control brain, caused cytoplasmic redistribution of TDP-43, suggesting that secreted exosomes might contribute to propagation of TDP-43 proteinopathy. Yet, inhibition of exosome secretion by inactivation of neutral sphingomyelinase 2 with GW4869 or by silencing RAB27A provoked formation of TDP-43 aggregates in Neuro2a cells. Moreover, administration of GW4869 exacerbated the disease phenotypes of transgenic mice expressing human TDP-43(A315T) mutant. Thus, even though results suggest that exosomes containing pathological TDP-43 may play a key role in the propagation of TDP-43 proteinopathy, a therapeutic strategy for amyotrophic lateral sclerosis based on inhibition of exosome production would seem inappropriate, as in vivo data suggest that exosome secretion plays an overall beneficial role in neuronal clearance of pathological TDP-43.