A role of BAG3 in regulating SNCA/α-synuclein clearance via selective macroautophagy
A role of BAG3 in regulating SNCA/α-synuclein clearance via selective macroautophagy
复制标题
BAG3 通过选择性巨自噬调节 SNCA/α-突触核蛋白清除的作用
DOI：
10.1016/j.neurobiolaging.2017.08.023
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发表时间：
2017-12-01
影响因子：
4.2
通讯作者：
Liu, Chun-Feng
中科院分区：
文献类型：
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作者：
Cao, Yu-Lan;Yang, Ya-Ping;Liu, Chun-Feng
许多研究表明，BAG3通过宏观自噬在调节蛋白质降解过程中起着关键作用。然而，目前尚不清楚BAG3是否影响帕金森病相关蛋白α-突触核蛋白(SNCA)的质量控制。在这项研究中，我们证明了BAG3在SNCA(A53T)转基因小鼠的腹侧中脑以及MG132处理的过表达野生型SNCA(SNCA(WT)-PC12)的PC12细胞中的表达增加。此外，我们还发现，在SNCA(WT)-PC12细胞中，BAG3的过表达足以增强自噬活性，而Bag3的敲除则降低了自噬活性。免疫沉淀显示BAG3与热休克蛋白70和隔离体1相互作用。免疫组织化学染色还显示BAG3与这两种蛋白以及Lc3点在SNCAA53T小鼠中脑内酪氨酸羟基酶阳性神经元中的核周聚集和共存。BAG3过表达能够通过宏自噬调节SNCA的降解，而ATG5基因敲除可以阻止这种自噬。综上所述，这些结果表明BAG3通过巨噬作用调节SNCA清除，热休克蛋白70-BAG3-隔离小体1复合体可能参与了这一过程。(C)2017 Elsevier Inc.保留所有权利。
Many studies reveal that BAG3 plays a critical role in the regulation of protein degradation via macro-autophagy. However, it remains unknown whether BAG3 affects the quality control of alpha-synuclein (SNCA), a Parkinson's disease-related protein. In this study, we demonstrated the increases of BAG3 expression in the ventral midbrain of SNCA(A53T) transgenic mice and also in MG132-treated PC12 cells overexpressing wild-type SNCA (SNCA(WT)-PC12). Moreover, we showed that BAG3 overexpression was sufficient to enhance the autophagy activity while knockdown of Bag3 reduced it in SNCA(WT)-PC12 cells. Immunoprecipitation revealed that BAG3 interacted with heat shock protein 70 and sequestosome 1. The immunostaining also showed the perinuclear accumulation and colocalization of BAG3 with these 2 proteins, as well as with LC3 dots in tyrosine hydroxylase-positive neurons in the midbrain of SNCAA53T mice. BAG3 overexpression was able to modulate SNCA degradation via macroautophagy which was prevented by Atg5 knockdown. Taken together, these results indicate that BAG3 plays a relevant role in regulating SNCA clearance via macroautophagy, and the heat shock protein 70-BAG3-sequestosome 1 complex may be involved in this process. (C) 2017 Elsevier Inc. All rights reserved.