Loss of Drosha underlies dopaminergic neuron toxicity in models of Parkinson's disease

• Type of Material: Article
• Authors: Ronglin Wang, Fourth Military Medical University; Fangfang Lu, Fourth Military Medical University; Gang Zhu, Fourth Military Medical University; Dayun Feng, Fourth Military Medical University; Tiejian Nie, Fourth Military Medical University; Kai Tao, Fourth Military Medical University; Shaosong Yang, Fourth Military Medical University; Jie Lei, Fourth Military Medical University; Lu Huang, Fourth Military Medical University; Zixu Mao, Emory University; Qian Yang, Fourth Military Medical University
• Language: English
• Date: 2018-06-07
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2018
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41419-018-0716-5
• Title of Journal or Parent Work: Cell Death and Disease
• ISSN: 2041-4889
• Volume: 9
• Issue: 6
• Start Page: 693
• End Page: 693
• Grant/Funding Information: This work was supported by Projects of International Cooperation and Exchanges NSFC, grant No. 81720108016 (QY), by The National Key Research and Development Program of China, grant No. 2016YFC1306603 (Q.Y), by the National Natural Science Foundation of China, grant No. 31671060 (Q.Y), and by NIH NS095269 (Z.M).
• Keywords: MICRORNA BIOGENESIS; MICE; SURVIVAL FACTOR MEF2D; ACTIVATION; Cell Biology; DOWN-REGULATION; Life Sciences & Biomedicine; MOTOR; Science & Technology; NEURODEGENERATIVE DISEASES; DEATH; OXIDATIVE STRESS; MOUSE MODEL
• Research Categories: Health Sciences, Pharmacology; Biology, Cell; Biology, Neuroscience

Abstract

MiRNAs, a group of powerful modulator of gene expression, participate in multiple cellular processes under physiological and pathological conditions. Emerging evidence shows that Drosha, which controls the initial step in canonical miRNA biogenesis, is involved in modulating cell survival and death in models of several diseases. However, the role of Drosha in Parkinson's disease (PD) has not been well established. Here, we show that the level of Drosha decreases in 6-OHDA-induced cellular and animal models of PD. 6-OHDA induced a p38 MAPK-dependent phosphorylation of Drosha. This triggered Drosha degradation. Enhancing the level of Drosha protected the dopaminergic (DA) neurons from 6-OHDA-induced toxicity in both in vitro and in vivo models of PD and alleviated the motor deficits of PD mice. These findings reveal that Drosha plays a critical role in the survival of DA neurons and suggest that stress-induced destabilization of Drosha may be part of the pathological process in PD.