Exosomal secretion of α-synuclein as protective mechanism after upstream blockage of macroautophagy.
Exosomal secretion of α-synuclein as protective mechanism after upstream blockage of macroautophagy.
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DOI：
10.1038/s41419-018-0816-2
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发表时间：
2018-07-09
影响因子：
9
通讯作者：
Höglinger GU
中科院分区：
文献类型：
--
作者：
Fussi N;Höllerhage M;Chakroun T;Nykänen NP;Rösler TW;Koeglsperger T;Wurst W;Behrends C;Höglinger GU
病理性α-突触核蛋白聚集体的积累在帕金森病中起主要作用。大自噬是一种降解细胞内蛋白质聚集体的机制，通过将它们包裹到自噬体中，然后与溶酶体融合。我们之前已经证明，在人类神经元中，大自噬的药理学激活可以防止α-突触核蛋白诱导的毒性。在这里，我们假设抑制大自噬会加重α-突触核蛋白诱导的细胞死亡。出乎意料的是，通过沉默ATG 5抑制自噬体形成保护了α-突触核蛋白诱导的毒性。因此，我们研究了替代的细胞机制，以弥补宏自噬的损失。ATG 5沉默不影响泛素-蛋白酶体系统、伴侣系统、伴侣介导的自噬或未折叠蛋白反应。然而，ATG 5沉默增加了α-突触核蛋白通过外泌体的分泌。阻断外泌体分泌会加剧α-突触核蛋白诱导的细胞死亡。我们的结论是，自噬体形成受损后，α-突触核蛋白的外泌体分泌增加，以减少细胞内α-突触核蛋白的负荷。这种代偿机制防止α-突触核蛋白诱导的神经元细胞死亡。
Accumulation of pathological α-synuclein aggregates plays a major role in Parkinson’s disease. Macroautophagy is a mechanism to degrade intracellular protein aggregates by wrapping them into autophagosomes, followed by fusion with lysosomes. We had previously shown that pharmacological activation of macroautophagy protects against α-synuclein-induced toxicity in human neurons. Here, we hypothesized that inhibition of macroautophagy would aggravate α-synuclein-induced cell death. Unexpectedly, inhibition of autophagosome formation by silencing of ATG5 protected from α-synuclein-induced toxicity. Therefore, we studied alternative cellular mechanisms to compensate for the loss of macroautophagy. ATG5 silencing did not affect the ubiquitin–proteasome system, chaperone systems, chaperone-mediated autophagy, or the unfolded protein response. However, ATG5 silencing increased the secretion of α-synuclein via exosomes. Blocking exosomal secretion exacerbated α-synuclein-induced cell death. We conclude that exosomal secretion of α-synuclein is increased after impaired formation of autophagosomes to reduce the intracellular α-synuclein burden. This compensatory mechanism prevents α-synuclein-induced neuronal cell death.
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DOI：
10.1073/pnas.1521230113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Kowal, Joanna;Arras, Guillaume;Thery, Clotilde
通讯作者：
Thery, Clotilde
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
5.4
作者：
Klein, Christine;Westenberger, Ana
通讯作者：
Westenberger, Ana
影响因子：
30.8
作者：
Chang D;Nalls MA;Hallgrímsdóttir IB;Hunkapiller J;van der Brug M;Cai F;International Parkinson's Disease Genomics Consortium;23andMe Research Team;Kerchner GA;Ayalon G;Bingol B;Sheng M;Hinds D;Behrens TW;Singleton AB;Bhangale TR;Graham RR
通讯作者：
Graham RR
影响因子：
16.2
作者：
Bendor JT;Logan TP;Edwards RH
通讯作者：
Edwards RH