Long non-coding RNA TUG1 induces ferroptosis in hippocampal neurons and depressive-like behaviors by facilitating the ubiquitination of DUSP14

Abstract

Abstract Background Previous research has established that long non-coding RNAs (lncRNAs) play an important role in major depressive disorder (MDD; however, the underlying effects of lncRNA Taurine Upregulated Gene 1 (TUG1) on MDD have yet to be fully evaluated. Here, we investigated how TUG1 triggers the dysfunction of neurons and depressive-like behaviors and determined the molecular mechanisms involved. Methods The expression levels of TUG1 were determined in the serum samples of MDD patients by high-throughput RNA sequencing. Then, we investigated the function of TUG1 in MDD by microinjecting TUG1 lentivirus into the hippocampi of experimental mice. In addition, neuronal ferroptosis was investigated by determining the levels of ROS, GSH, and MDA. Finally, interactions between TUG1 and DUSP14 protein were validated by RNA immunoprecipitation and DUSP14 ubiquitination in neurons was analyzed by co-immunoprecipitation. Results TUG1 was significantly increased in the hippocampal tissues of CUS mice and the peripheral blood of MDD patients and had important clinical significance for diagnosing MDD. The knockdown of TUG1 notably ameliorated hippocampal ferroptosis and depressive-like behaviors triggered by CUS. In vitro, low expression levels of TUG1 attenuated the neuronal ferroptosis induced by corticosterone by promoting the expression of DUSP14 and GPX4 expresion. Moreover, The overexpression of both DUSP14 and GPX4 reduced neuronal ferroptosis in cells overexpressing DUSP14. Mechanistically, TUG1 interacts with DUSP14 to facilitate its ubiquitination and trigger its degradation. Conclusion Our data define the functional link between TUG1 and ferroptosis in the context of MDD and suggest that TUG1 may represent a novel therapeutic target for MDD.