期刊
NEUROBIOLOGY OF AGING
卷 60, 期 -, 页码 104-115出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2017.08.023
关键词
BAG3; Hsp70; Macroautophagy; SNCA; SQSTM1
资金
- National Key R&D Program of China [2016YFC1306000]
- National Natural Science Foundation of China [81301091, 81671250, 91649114]
- Jiangsu Provincial Special Program of Medical Science [BL2014042]
- Youth Fund of Jiangsu Province's Nature Science Foundation [BK20170355]
- Jiangsu Provincial Medical Key Discipline Project [ZDXKB2016022]
- Suzhou Clinical Research Center of Neurological Disease [Szzx201503]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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.
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