Abstract
Parkinson’s disease (PD) is characterized by dopaminergic neuronal loss and the presence of intra-neuronal Lewy body (LB) inclusions with aggregated α-synuclein (α-Syn) as the major component. MAOB, a crucial monoamine oxidase for dopamine metabolism, triggers oxidative stress in dopaminergic neurons and α-Syn aggregation. However, the key molecular mechanism that mediates PD pathogenesis remains elusive. Here we show that C/EBPβ acts as an age-dependent transcription factor for both α-Syn and MAOB, and initiates the PD pathologies by upregulating these two pivotal players, in addition to escalating δ-secretase activity to cleave α-Syn and promotes its neurotoxicity. Overexpression of C/EBPβ in human wild-type α-Syn transgenic mice facilitates PD pathologies and elicits motor disorders associated with augmentation of δ-secretase, α-Syn, and MAOB. In contrast, depletion of C/EBPβ from human α-Syn Tg mice abolishes rotenone-elicited PD pathologies and motor impairments via downregulating the expression of these key factors. Hence, our study supports that C/EBPβ/δ-secretase signaling mediates PD pathogenesis via regulating the expression and cleavage of α-Syn and MAOB.
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Acknowledgements
This work is supported by a grant from the National Institute of Health (RF1, AG051538; RO1, NS105982) to KY, the State Key Program of National Natural Science Foundation of China (No. 81330030) to LC, the National Key Research and Development Program of China (No. 2016YFA0100800) to LC, the Fundamental Research Funds for the Central Universities of China (No. 22120170273) to LC, the National Natural Science Foundation (NSFC) of China (No. 81301042) to ZW, and the Shanghai Pujiang Talent Program, China (No. 19PJ1409200) to ZW. The authors are thankful to Dr Arthur W. English at Department of Cell Biology, Emory University for his critical reading of the manuscript. This study was supported in part by the Rodent Behavioral Core, which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities (P30NS055077). Further support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. HPLC study was supported in part by the Emory HPLC Bioanalytical Core, which was supported by the Department of Pharmacology, Emory University School of Medicine and the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.
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KY conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. ZW designed and performed most of the experiments and analyzed the data. YX prepared human PD-iPSCs and the ChIP assay in rat primary neuron. Z-HW preformed the tests in adult and aged Cebpb+/+/Cebpb−/− mice. SSK performed immunochemistry staining. KL and XL prepared primary neurons and assisted with in vivo and in vitro experiments. LJ, XW, and LC assisted with data analysis and interpretation and critically read the manuscript.
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Wu, Z., Xia, Y., Wang, Z. et al. C/EBPβ/δ-secretase signaling mediates Parkinson’s disease pathogenesis via regulating transcription and proteolytic cleavage of α-synuclein and MAOB. Mol Psychiatry 26, 568–585 (2021). https://doi.org/10.1038/s41380-020-0687-7
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DOI: https://doi.org/10.1038/s41380-020-0687-7
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