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Published on: October 28, 2019
Mir143-BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: Implications for
Yuan Zhang1, Kai Shen1, Ying Bai1
1a Department of Pharmacology , School of Medicine, Southeast University , Nanjing , Jiangsu , China.
Abstract:
BBC3 (BCL2 binding component 3) is a known apoptosis inducer; however, its role in microglial survival remains poorly understood. In addition to the classical transcription factor TRP53, Mir143 is involved in BBC3 expression at the post-transcriptional level. Here, we identify unique roles of Mir143-BBC3 in mediating microglial survival via the regulation of the interplay between apoptosis and autophagy. Autophagy inhibition accelerated methamphetamine-induced apoptosis, whereas autophagy induction attenuated the decrease in microglial survival. Moreover, anti-Mir143-dependent BBC3 upregulation reversed the methamphetamine-induced decrease in microglial survival via the regulation of apoptosis and autophagy. The in vivo relevance of these findings was confirmed in mouse models, which demonstrated that the microinjection of anti-Mir143 into the hippocampus ameliorated the methamphetamine-induced decrease in microglia as well as that observed in heterozygous Mir143(+/-) mice. These findings provide new insight regarding the specific contributions of Mir143-BBC3 to microglial survival in the context of drug abuse.
Insights
MicroRNA-143 (Mir143) and BCL2 binding component 3 (BBC3) regulate microglial survival by balancing apoptosis and autophagy. Targeting Mir143-BBC3 may protect microglia from drug abuse-induced damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- BCL2 binding component 3 (BBC3) is an apoptosis inducer, but its function in microglial survival is unclear.
- MicroRNA-143 (Mir143) influences BBC3 expression post-transcriptionally, alongside the transcription factor TRP53.
Purpose of the Study:
- To investigate the roles of Mir143-BBC3 in microglial survival, focusing on the interplay between apoptosis and autophagy.
- To determine the therapeutic potential of targeting the Mir143-BBC3 pathway in methamphetamine-induced neurotoxicity.
Main Methods:
- Investigated microglial survival under methamphetamine exposure with manipulated autophagy and Mir143 levels.
- Utilized in vitro cell cultures and in vivo mouse models (hippocampal microinjection, heterozygous Mir143 mice).
- Assessed apoptosis and autophagy markers to understand the regulatory mechanisms.
Main Results:
- Autophagy inhibition worsened methamphetamine-induced microglial apoptosis; autophagy induction improved survival.
- Upregulating BBC3 via anti-Mir143 treatment protected microglia from methamphetamine-induced cell death.
- In vivo studies confirmed that anti-Mir143 administration ameliorated microglial loss in methamphetamine-exposed mice and Mir143(+/-) mice.
Conclusions:
- The Mir143-BBC3 axis plays a critical role in mediating microglial survival by modulating apoptosis and autophagy.
- Targeting Mir143-BBC3 offers a potential therapeutic strategy for neuroprotection in drug abuse contexts.
