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

• DOI: 10.1038/s41419-018-0716-5
• Publication Date: 2018-06-07T10:25:00Z
• Authors: Ronglin Wang; Fangfang Lu; Gang Zhu; Dayun Feng; Tiejian Nie; Kai Tao; Shaosong Yang; Jie Lei; Lu Huang; Zixu Mao; Qian Yang
• Keywords: Male; Ribonuclease III; 0301 basic medicine; Protein Stability; Dopaminergic Neurons; Parkinson Disease; Motor Activity; p38 Mitogen-Activated Protein Kinases; Article; Cell Line; Mice, Inbred C57BL; Disease Models, Animal; 03 medical and health sciences; Proteolysis; Animals; Phosphorylation; Oxidopamine

AbstractMiRNAs, 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.