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

• Published in: British journal of pharmacology 2018-02, Vol.175 (4), p.590-605
• Main Authors: Zhang, Zhao, Chu, Shi‐Feng, Wang, Sha‐Sha, Jiang, Yi‐Na, Gao, Yan, Yang, Peng‐Fei, Ai, Qi‐Di, Chen, Nai‐Hong
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; alpha-Synuclein - metabolism; Animals; Autophagy; Computer simulation; Corticosterone; Deoxyribonucleic acid; DNA; DNA damage; DNA-Binding Proteins - metabolism; Dopamine; Dopamine receptors; Electrochemistry; Endoplasmic reticulum; High-performance liquid chromatography; Humans; Immunofluorescence; Inhibition; Liquid chromatography; Male; Mice; Mice, Transgenic; miRNA; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - psychology; Parkinson's disease; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; Parkinsonian Disorders - psychology; PC12 Cells; Phagocytosis; Proteasomes; Rats; Research Paper; Research Papers; Restraint, Physical; Rodents; Stress; Stress, Psychological - metabolism; Stress, Psychological - pathology; Stress, Psychological - psychology; Substantia nigra; Synuclein; Transcription; Transcription Factors - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14091

Background and Purpose Recently, the incidence of Parkinson's disease has shown a tendency to move to a younger population, linked to the constantly increasing stressors of modern society. However, this relationship remains obscure. Here, we have investigated the contribution of stress and the mechanisms underlying this change. Experimental Approach Ten‐month‐old α‐synuclein A53T mice, a model of Parkinson's disease (PD), 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 in vitro. We used Western blot, microRNA expression analysis, immunofluorescence staining, dual luciferase reporter assay and HPLC electrochemical detection to assess cellular and molecular networks after stress treatment. In vivo, stereotaxic injection of shRNA lentivirus was used to confirm our in vitro results. Key Results The protein RTP801 is encoded by DNA‐damage‐inducible transcript 4, and it was specifically increased in dopaminergic neurons of the substantia nigra after CRS treatment. RTP801 was post‐transcriptionally inhibited by the down‐regulation of miR‐7. Delayed turnover of RTP801, through the inhibition of proteasome degradation also contributed to its high content. Elevated RTP801 blocked autophagy, thus increasing accumulation of oligomeric α‐synuclein and aggravating endoplasmic reticulum stress. RTP801 inhibition alleviated the symptoms of neurodegeneration during this process. Conclusions and Implications RTP801 is a promising target for the treatment of PD, especially for PD‐sensitive patients who live under increased social pressure. Down‐regulation of RTP801 could inhibit the current tendency to an earlier onset of PD.