6-OHDA Induces Oxidation of F-box Protein Fbw7β by Chaperone-Mediated Autophagy in Parkinson's Model.

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.