主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Background
Mounting evidence suggests that chronic stress exacerbates Parkinson's disease (PD), which is meaningful in clarifying the relationship between constantly increased stress and its earlier onset age in the modern society, while the mechanism is still obscure. We performed our study to check the executor in this process.
Methods
Ten month old A53T a-synuclein mice were treated with chronic restraint stress (CRS). PD-like behavioral test and pathological changes were tested. In vitro, differentiated PC12-A53T cells were treated with CORT. Various approaches were used to assess whether RTP801 mediated neurodegeneration after stress treatment, including western blot, microRNA expression analysis, immunofluorescence staining, dual luciferase reporter assay, HPLC-ECD test. In vivo stereotaxic injection of RTP801 shRNA lentivirus was also applied to verify our work.
Results
RTP801 was specificity elevated in substantia nigra dopaminergic neurons after CRS treatment. The downregulation of miR-7, which post-transcriptionally inhibited the expression of RTP801, and the retard of proteasome degradation, which delayed the turnover of RTP801, both contributed to the high content of RTP801. Elevated RTP801 triggered autophagic obstacle, which promoted more accumulation of oligomeric a-synuclein, and also aggravated endoplasmic reticulum stress. RTP801 inhibition attenuated the above disorders, and alleviated neurodegeneration in this process.
Conclusions
The elevated RTP801 in dopaminergic neurons induced by CRS treatment might be a promising anti-PD candidate for those PD sensitive patients constantly living with great social pressure. RTP801 regulation might also benefit for the younger morbidity tendency of PD nowadays.
