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Mitochondrial dysfunction triggers the pathogenesis of Parkinson’s disease in neuronal C/EBPβ transgenic mice

Molecular Psychiatry volume 26, pages 7838–7850 (2021)Cite this article

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Abstract

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/EBPβ 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/EBPβ/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBPβ 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/EBPβ mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBPβ/AEP pathway.

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Fig. 1: Screening for mitochondrial inhibitors escalating ROS and activating C/EBPβ/AEP pathway.
Fig. 2: TTFA triggers mitochondrial dysfunctions, stimulating C/EBPβ/AEP signaling.
Fig. 3: Chronic treatment of ETC inhibitors induces motor deficits in Thy1-C/EBPβ transgenic mice.
Fig. 4: Chronic treatment of ETC inhibitors induces dopaminergic neuronal loss and α-Syn aggregation in the gut of Thy1-C/EBPβ transgenic mice.
Fig. 5: Chronic treatment of ETC inhibitors induces PD pathologies in the brains of Thy1-C/EBPβ transgenic mice.
Fig. 6: Deletion of SDHD in the SN of Thy1-C/EBPβ transgenic mice induces motor defects.
Fig. 7: Depletion of SDHD in the SN triggers dopaminergic neuronal loss and PD pathologies in Thy1-C/EBPβ transgenic mice.

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All data and materials used are available in the main text or as supplementary materials. The authors will also provide data and materials upon request. Source data are provided with this paper.

References

  1. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.

    Article  CAS  PubMed  Google Scholar 

  2. Faustini G, Bono F, Valerio A, Pizzi M, Spano P, Bellucci A. Mitochondria and alpha-synuclein: friends or foes in the pathogenesis of parkinson’s disease? Genes (Basel) 2017;8:377–85.

    Article  Google Scholar 

  3. Gao F, Yang J, Wang D, Li C, Fu Y, Wang H, et al. Mitophagy in Parkinson’s disease: pathogenic and therapeutic implications. Front Neurol. 2017;8:527.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Pozo Devoto VM, Falzone TL. Mitochondrial dynamics in Parkinson’s disease: a role for alpha-synuclein? Dis Model Mech. 2017;10:1075–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Grunewald A, Kumar KR, Sue CM. New insights into the complex role of mitochondria in Parkinson’s disease. Prog Neurobiol. 2019;177:73–93.

    Article  CAS  PubMed  Google Scholar 

  6. Keeney PM, Xie J, Capaldi RA, Bennett JP Jr. Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 2006;26:5256–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sato T, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun. 1989;163:1450–5.

    Article  CAS  PubMed  Google Scholar 

  8. Blesa J, Przedborski S. Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat. 2014;8:155.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Storch A, Ludolph AC, Schwarz J. Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration. J Neural Transm (Vienna). 2004;111:1267–86.

    Article  CAS  Google Scholar 

  10. Desai VG, Feuers RJ, Hart RW, Ali SF. MPP(+)-induced neurotoxicity in mouse is age-dependent: evidenced by the selective inhibition of complexes of electron transport. Brain Res. 1996;715:1–8.

    Article  CAS  PubMed  Google Scholar 

  11. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci. 1985;36:2503–8.

    Article  CAS  PubMed  Google Scholar 

  12. Jackson-Lewis V, Blesa J, Przedborski S. Animal models of Parkinson’s disease. Parkinsonism Relat Disord. 2012;18:S183–185.

    Article  PubMed  Google Scholar 

  13. Sterneck E, Johnson PF. CCAAT/enhancer binding protein beta is a neuronal transcriptional regulator activated by nerve growth factor receptor signaling. J Neurochem. 1998;70:2424–33.

    Article  CAS  PubMed  Google Scholar 

  14. Nadeau S, Hein P, Fernandes KJ, Peterson AC, Miller FD. A transcriptional role for C/EBP beta in the neuronal response to axonal injury. Mol Cell Neurosci. 2005;29:525–35.

    Article  CAS  PubMed  Google Scholar 

  15. Alberini CM, Ghirardi M, Metz R, Kandel ER. C/EBP is an immediate-early gene required for the consolidation of long-term facilitation in Aplysia. Cell. 1994;76:1099–114.

    Article  CAS  PubMed  Google Scholar 

  16. Taubenfeld SM, Milekic MH, Monti B, Alberini CM. The consolidation of new but not reactivated memory requires hippocampal C/EBPbeta. Nat Neurosci. 2001;4:813–8.

    Article  CAS  PubMed  Google Scholar 

  17. Poli V. The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J Biol Chem. 1998;273:29279–82.

    Article  CAS  PubMed  Google Scholar 

  18. Wu Z, Xia Y, Wang Z, Su Kang S, Lei K, Liu X, et al. C/EBPbeta/delta-secretase signaling mediates Parkinson’s disease pathogenesis via regulating transcription and proteolytic cleavage of alpha-synuclein and MAOB. Mol Psychiatry. 2021;26:568–85.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang Z, Kang SS, Liu X, Ahn EH, Zhang Z, He L, et al. Asparagine endopeptidase cleaves alpha-synuclein and mediates pathologic activities in Parkinson’s disease. Nat Struct Mol Biol. 2017;24:632–42.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kang SS, Ahn EH, Zhang Z, Liu X, Manfredsson FP, Sandoval IM, et al. alpha-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson’s disease. EMBO J. 2018;37:1–19.

    Article  Google Scholar 

  21. Wang ZH, Gong K, Liu X, Zhang Z, Sun X, Wei ZZ, et al. C/EBPbeta regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nat Commun. 2018;9:1784.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lei K, Gu X, Alvarado AG, Du Y, Luo S, Ahn EH, et al. Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma. J Hematol Oncol. 2020;13:1–21.

    Article  Google Scholar 

  23. Edgington LE, Verdoes M, Ortega A, Withana NP, Lee J, Syed S, et al. Functional imaging of legumain in cancer using a new quenched activity-based probe. J Am Chem Soc. 2013;135:174–82.

    Article  CAS  PubMed  Google Scholar 

  24. Cortes-Canteli M, Pignatelli M, Santos A, Perez-Castillo A. CCAAT/enhancer-binding protein beta plays a regulatory role in differentiation and apoptosis of neuroblastoma cells. J Biol Chem. 2002;277:5460–7.

    Article  CAS  PubMed  Google Scholar 

  25. Cortes-Canteli M, Aguilar-Morante D, Sanz-Sancristobal M, Megias D, Santos A, Perez-Castillo A. Role of C/EBPbeta transcription factor in adult hippocampal neurogenesis. PLoS One. 2011;6:e24842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Goto K, Kato G, Kawahara I, Luo Y, Obata K, Misawa H, et al. In vivo imaging of enteric neurogenesis in the deep tissue of mouse small intestine. PLoS One. 2013;8:e54814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Araujo FG, Lin T, Remington JS. The activity of atovaquone (566C80) in murine toxoplasmosis is markedly augmented when used in combination with pyrimethamine or sulfadiazine. J Infect Dis. 1993;167:494–7.

    Article  CAS  PubMed  Google Scholar 

  28. Xiao WH, Bennett GJ. Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin. Pain. 2012;153:704–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rosen ED. The transcriptional basis of adipocyte development. Prostaglandins Leukot Ess Fat Acids. 2005;73:31–34.

    Article  CAS  Google Scholar 

  30. Millward CA, Heaney JD, Sinasac DS, Chu EC, Bederman IR, Gilge DA, et al. Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta are protected against diet-induced obesity. Diabetes. 2007;56:161–7.

    Article  CAS  PubMed  Google Scholar 

  31. Ahn EH, Kang SS, Liu X, Chen G, Zhang Z, Chandrasekharan B, et al. Initiation of Parkinson’s disease from gut to brain by delta-secretase. Cell Res. 2020;30:70–87.

    Article  PubMed  Google Scholar 

  32. Musgrove RE, Helwig M, Bae EJ, Aboutalebi H, Lee SJ, Ulusoy A, et al. Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular alpha-synuclein transfer. J Clin Invest. 2019;129:3738–53.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lei K, Xia Y, Wang X-C, Ahn EH, Jin L, Ye K. C/EBPβ mediates NQO1 and GSTP1 anti-oxidative reductases expression in glioblastoma, promoting brain tumor proliferation. Redox Biol. 2020;34:101578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lei K, Kang SS, Ahn EH, Chen C, Liao J, Liu X, et al. C/EBPβ/AEP signaling regulates the oxidative stress in malignant cancers, stimulating the metastasis. Mol Cancer Ther. 2021;9:1–13.

    Google Scholar 

  35. Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005;121:1043–57.

    Article  CAS  PubMed  Google Scholar 

  36. Moreno-Sanchez R, Hernandez-Esquivel L, Rivero-Segura NA, Marin-Hernandez A, Neuzil J, Ralph SJ, et al. Reactive oxygen species are generated by the respiratory complex II-evidence for lack of contribution of the reverse electron flow in complex I. FEBS J. 2013;280:927–38.

    CAS  PubMed  Google Scholar 

  37. Gutteridge WE. 566C80, an antimalarial hydroxynaphthoquinone with broad spectrum: experimental activity against opportunistic parasitic infections of AIDS patients. J Protozool. 1991;38:141S–143S.

    CAS  PubMed  Google Scholar 

  38. Sun IL, Sun EE, Crane FL, Morre DJ, Lindgren A, Low H. Requirement for coenzyme Q in plasma membrane electron transport. Proc Natl Acad Sci USA. 1992;89:11126–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J Biol Chem. 1997;272:3961–6.

    Article  CAS  PubMed  Google Scholar 

  40. Takabe H, Warnken ZN, Zhang Y, Davis DA, Smyth HDC, Kuhn JG, et al. A repurposed drug for brain cancer: enhanced atovaquone amorphous solid dispersion by combining a spontaneously emulsifying component with a polymer carrier. Pharmaceutics. 2018;10:1–20.

    Article  Google Scholar 

  41. Symersky J, Osowski D, Walters DE, Mueller DM. Oligomycin frames a common drug-binding site in the ATP synthase. Proc Natl Acad Sci USA. 2012;109:13961–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Han SY, Jeong YJ, Choi Y, Hwang SK, Bae YS, Chang YC. Mitochondrial dysfunction induces the invasive phenotype, and cell migration and invasion, through the induction of AKT and AMPK pathways in lung cancer cells. Int J Mol Med. 2018;42:1644–52.

    CAS  PubMed  Google Scholar 

  43. Tettamanti G, Malagoli D, Marchesini E, Congiu T, de Eguileor M, Ottaviani E. Oligomycin A induces autophagy in the IPLB-LdFB insect cell line. Cell Tissue Res. 2006;326:179–86.

    Article  CAS  PubMed  Google Scholar 

  44. Vaamonde-Garcia C, Loureiro J, Valcarcel-Ares MN, Riveiro-Naveira RR, Ramil-Gomez O, Hermida-Carballo L, et al. The mitochondrial inhibitor oligomycin induces an inflammatory response in the rat knee joint. BMC Musculoskelet Disord. 2017;18:254.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from NIH grant (RF1, AG051538) to K.Y. We thank ADRC at Emory University for human PD patients and healthy control samples. This study was supported in part by the Rodent Behavioral Core (RBC), 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, Hallym University Research Fund, 2021(HRF-202103-009), National Key R&D Program of China (2018YFC1314700), National Natural Science Foundation of China (81974196, 81873779) and Program of Shanghai Academic Research Leader (20XD1403400). Dr. Kecheng Lei was supported by grants from China Postdoctoral Science Foundation (2018M632168).

Author contributors

KY conceived the project, designed the experiments, analyzed the data and wrote the manuscript. EHA and KL designed and performed most of the experiments. SSK, XL prepared SH-SY5Y cells and assessed animal experiments. ZHW assisted with data analysis. WH and YTW provided important reagents and scientific discussion. LEM and LJ critically read the manuscript.

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Author notes

  1. These authors contributed equally: Eun Hee Ahn, Kecheng Lei.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Eun Hee Ahn, Kecheng Lei, Seong Su Kang, Zhi-Hao Wang, Xia Liu & Keqiang Ye

  2. Department of Physiology, Hallym University College of Medicine, Chuncheon, Republic of Korea

    Eun Hee Ahn

  3. Neurotoxin research center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, P. R. China

    Kecheng Lei & Lingjing Jin

  4. The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institution, Shenzhen, China

    Wei Hong

  5. Faculty of Life and Health Sciences, Shenzhen Institutite of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Yu Tian Wang

  6. Department of Medicine and DM Center for Brain Health, University of British Columbia, Vancouver, BC, Canada

    Yu Tian Wang

  7. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia

    Laura E. Edgington-Mitchell

  8. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Laura E. Edgington-Mitchell

  9. Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, Bluestone Center for Clinical Research, New York, New York, NY, USA

    Laura E. Edgington-Mitchell

  10. Neurorehabilitation Center of Yangzhi Rehabilitation Hospital, Tongji Univeirsity School of Medicine. No. 2209 Guangxing Rd, Songjiang Disc, Shanghai, China

    Lingjing Jin

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Ahn, E.H., Lei, K., Kang, S.S. et al. Mitochondrial dysfunction triggers the pathogenesis of Parkinson’s disease in neuronal C/EBPβ transgenic mice. Mol Psychiatry 26, 7838–7850 (2021). https://doi.org/10.1038/s41380-021-01284-x

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