British Journal of Pharmacology
British Journal of Pharmacology
5 years ago

RTP801 is a critical factor in the neurodegeneration process of A53T alpha-synuclein in a mouse model of Parkinson's disease under chronic restraint stress

Qi-Di Ai, Yi-Na Jiang, Sha-Sha Wang, Shi-Feng Chu, Yan Gao, Zhao Zhang, Nai-Hong Chen, Peng-Fei Yang
BACKGROUND AND PURPOSE The incidence of Parkinson's disease exhibited a younger tendency in recent years with the constantly increased stressors of modern society, but this relationship remains obscured. We performed this study to investigate whether stress contributes to this tendency and identify the executor during this process. EXPERIMENTAL APPROACH Ten-month-old α-synuclein A53T mice, a PD mice model, were treated with chronic restraint stress (CRS) to simulate a PD-sensitive person with constant stress stimulation. PD-like behavioural tests and pathological changes were evaluated. Differentiated PC12-A53T cells were treated with corticosterone (CORT) in vitro. We used Western blot, microRNA expression analysis, immunofluorescence staining, dual luciferase reporter assay, and HPLC-ECD to assess cellular and molecular networks after stress treatment. In vivo stereotaxic injection of shRNA lentivirus was used to verify our work. KEY RESULTS RTP801 is encoded by DNA-damage-inducible transcript 4 (Ddit4), and it was specificity triggered in substantia nigra dopaminergic neurons after CRS treatment. Further study revealed that RTP801 was post-transcriptionally inhibited via the downregulation of miR-7. Delayed turnover of RTP801 via the retarding of proteasome degradation also contributed to its high content. Elevated RTP801 triggered an autophagy obstacle, which increased the accumulation of oligomeric α-synuclein and further aggravated endoplasmic reticulum stress. RTP801 inhibition alleviated the symptoms of neurodegeneration during this process. CONCLUSIONS AND IMPLICATIONS Our studies revealed RTP801 as a promising anti-PD candidate, especially for PD-sensitive patients who constantly live under great social pressure. RTP801 regulation may be a benefit for the current younger morbidity tendency of PD.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14091

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