期刊
MOLECULAR PSYCHIATRY
卷 26, 期 12, 页码 7838-7850出版社
SPRINGERNATURE
DOI: 10.1038/s41380-021-01284-x
关键词
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资金
- NIH [AG051538]
- Rodent Behavioral Core (RBC) - Emory University School of Medicine
- Viral Vector Core of the Emory Neuroscience NINDS Core Facilities [P30NS055077]
- Georgia Clinical & Translational Science Alliance of the National Institutes of Health [UL1TR002378]
- Hallym University Research Fund [HRF-202103-009]
- National Key R&D Program of China [2018YFC1314700]
- National Natural Science Foundation of China [81974196, 81873779]
- Program of Shanghai Academic Research Leader [20XD1403400]
- China Postdoctoral Science Foundation [2018M632168]
Inhibition of complexes II or III in the mitochondrial electron transport chain leads to motor disorders and PD pathologies in mice, triggering dopaminergic neuronal cell death and activating the C/EBP beta/AEP pathway. Deletion of the SDHD gene in Substantia Nigra also results in ROS and PD pathologies, demonstrating that mitochondrial ETC inactivation plays a key role in PD pathogenesis.
Respiratory chain complex I deficiency elicits mitochondrial dysfunction and reactive oxidative species (ROS), which plays a crucial role in Parkinson's disease (PD) pathogenesis. However, it remains unclear whether the impairment in other complexes in the mitochondrial oxidative phosphorylation chain is also sufficient to trigger PD onset. Here we show that inhibition of Complex II or III in the electron transport chain (ETC) induces the motor disorder and PD pathologies in neuronal Thy1-C/EBP beta transgenic mice. Through a cell-based screening of mitochondrial respiratory chain inhibitors, we identified TTFA (complex II inhibitor) and Atovaquone (complex III inhibitor), which robustly block the oxidative phosphorylation functions, strongly escalate ROS, and activate C/EBP beta/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBP beta mice elicits constipation and motor defects, associated with Lewy body-like inclusions. Deletion of SDHD (Succinate dehydrogenase) gene from the complex II in the Substantia Nigra of Thy1-C/EBP beta mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBP beta/AEP pathway.
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