6-OHDA Induces Oxidation of F-box Protein Fbw7β by Chaperone-Mediated Autophagy in Parkinson’s Model
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Parkinson’s disease (PD) is the most common movement disorder disease, and its pathological feature is the degenerative loss of dopaminergic neurons in the substantia nigra compacta (SNc). In this study, we investigated whether distinct stress conditions target F-box protein Fbw7β via converging mechanisms. Our results showed that the 6-hyroxydopamine (6-OHDA), which causes PD in animals’ models, led to decreased stability of Fbw7β in DA neuronal SN4741 cells. Further experiments suggested that oxidized Fbw7β bound to heat-shock cognate protein 70 kDa, the key regulator for chaperone-mediated autophagy (CMA), at a higher affinity. Oxidative stress also increased the level of lysosomal-associated membrane protein 2A (LAMP2A), the rate-limiting receptor for CMA substrate flux, and stimulated CMA activity. These changes resulted in accelerated degradation of Fbw7β. 6-OHDA induced Fbw7β oxidation and increased LAMP2A in the SNc region of the mouse models. Consistently, the levels of oxidized Fbw7β were higher in postmortem PD brains compared with the controls. These findings for the first time revealed the specific mechanism of ubiquitin ligases, oxidative stress, and CMA-mediated protein degradation, to provide a new theoretical basis for further clarifying the mechanism of PD.
KeywordsChaperone-mediated autophagy Fbw7β Oxidative stress Parkinson’s disease Dopaminergic neurons
The authors thank Ms. Lin Zhang for her English proof reading. This project was supported by grant from the National Natural Science Foundation of China (81471377).
Xiufeng Wang, acquisition of data, literature research, and manuscript preparation; Heng Zhai, acquisition of data; Fang Wang, study concept and design, critical revision of the manuscript for important intellectual content, and study supervision.
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Conflict of Interest
The authors declare that they have no conflict of interest.
- 25.Ekholm-Reed S, Goldberg MS, Schlossmacher MG, Reed SI (2013) Parkin-dependent degradation of the F-box protein Fbw7beta promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol 33(18):3627–3643. doi: 10.1128/MCB.00535-13 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Cai Z, Zeng W, Tao K, E Zhen, Wang B, Yang Q (2015) Chaperone-mediated autophagy: roles in neuroprotection. Neurosci Bull 31 (4):452–458. doi: 10.1007/s12264-015-1540-x