Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson’s disease through mitochondrial dysfunction

Autoři: Chung-Yang Kao aff001;  Mafei Xu aff001;  Leiming Wang aff001;  Shih-Chieh Lin aff002;  Hui-Ju Lee aff001;  Lita Duraine aff005;  Hugo J. Bellen aff005;  David S. Goldstein aff010;  Sophia Y. Tsai aff001;  Ming-Jer Tsai aff001
Působiště autorů: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America aff001;  Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan aff002;  Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan aff003;  Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan aff004;  Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America aff005;  Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America aff006;  Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America aff007;  Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America aff008;  Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America aff009;  Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America aff010
Vyšlo v časopise: Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson’s disease through mitochondrial dysfunction. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008868
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008868


Parkinson’s disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.

Klíčová slova:

DNA methylation – Dopamine – Midbrain – Mitochondria – Mouse models – Neostriatum – Neurons – Parkinson disease


1. Borlongan CV, Burns J, Tajiri N, Stahl CE, Weinbren NL, Shojo H, et al. Epidemiological survey-based formulae to approximate incidence and prevalence of neurological disorders in the United States: a meta-analysis. PLoS ONE. 2013; 8: e78490. doi: 10.1371/journal.pone.0078490 24205243

2. Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the "common" neurologic disorders? Neurology. 2007; 68: 326–37. doi: 10.1212/01.wnl.0000252807.38124.a3 17261678

3. Giguere N, Burke Nanni S, Trudeau LE. On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease. Frontiers in neurology. 2018; 9: 455. doi: 10.3389/fneur.2018.00455 29971039

4. Di Stefano A, Sozio P, Cerasa LS, Iannitelli A. L-Dopa prodrugs: an overview of trends for improving Parkinson's disease treatment. Curr Pharm Des. 2011; 17: 3482–93. doi: 10.2174/138161211798194495 22074421

5. Michel PP, Hirsch EC, Hunot S. Understanding Dopaminergic Cell Death Pathways in Parkinson Disease. Neuron. 2016; 90: 675–91. doi: 10.1016/j.neuron.2016.03.038 27196972

6. Klein C, Schlossmacher MG. The genetics of Parkinson disease: Implications for neurological care. Nat Clin Pract Neurol. 2006; 2: 136–46. doi: 10.1038/ncpneuro0126 16932540

7. Klein C, Westenberger A. Genetics of Parkinson's disease. Cold Spring Harb Perspect Med. 2012; 2: a008888. doi: 10.1101/cshperspect.a008888 22315721

8. Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect. 2011; 119: 866–72. doi: 10.1289/ehp.1002839 21269927

9. Haelterman NA, Yoon WH, Sandoval H, Jaiswal M, Shulman JM, Bellen HJ. A mitocentric view of Parkinson's disease. Annu Rev Neurosci. 2014; 37: 137–59. doi: 10.1146/annurev-neuro-071013-014317 24821430

10. Cicchetti F, Drouin-Ouellet J, Gross RE. Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci. 2009; 30: 475–83. doi: 10.1016/j.tips.2009.06.005 19729209

11. Lotharius J, Brundin P. Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci. 2002; 3: 932–42. doi: 10.1038/nrn983 12461550

12. Tsang AH, Chung KK. Oxidative and nitrosative stress in Parkinson's disease. Biochim Biophys Acta. 2009; 1792: 643–50. doi: 10.1016/j.bbadis.2008.12.006 19162179

13. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson's disease. J Parkinsons Dis. 2013; 3: 461–91. doi: 10.3233/JPD-130230 24252804

14. Lin FJ, Qin J, Tang K, Tsai SY, Tsai MJ. Coup d'Etat: an orphan takes control. Endocr Rev. 2011; 32: 404–21. doi: 10.1210/er.2010-0021 21257780

15. Qin J, Wu SP, Creighton CJ, Dai F, Xie X, Cheng CM, et al. COUP-TFII inhibits TGF-beta-induced growth barrier to promote prostate tumorigenesis. Nature. 2013; 493: 236–40. doi: 10.1038/nature11674 23201680

16. Wu SP, Kao CY, Wang L, Creighton CJ, Yang J, Donti TR, et al. Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nat Commun. 2015; 6: 8245. doi: 10.1038/ncomms9245 26356605

17. Lin SC, Kao CY, Lee HJ, Creighton CJ, Ittmann MM, Tsai SJ, et al. Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer. Nat Commun. 2016; 7: 11418. doi: 10.1038/ncomms11418 27108958

18. Xie X, Tsai SY, Tsai MJ. COUP-TFII regulates satellite cell function and muscular dystrophy. J Clin Invest. 2016; 126: 3929–41. doi: 10.1172/JCI87414 27617862

19. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014; 46: 989–93. doi: 10.1038/ng.3043 25064009

20. Chang D, Nalls MA, Hallgrimsdottir IB, Hunkapiller J, van der Brug M, Cai F, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat Genet. 2017; 49: 1511–6. doi: 10.1038/ng.3955 28892059

21. Chai C, Lim KL. Genetic insights into sporadic Parkinson's disease pathogenesis. Curr Genomics. 2013; 14: 486–501. doi: 10.2174/1389202914666131210195808 24532982

22. Lesnick TG, Papapetropoulos S, Mash DC, Ffrench-Mullen J, Shehadeh L, de Andrade M, et al. A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genet. 2007; 3: e98. doi: 10.1371/journal.pgen.0030098 17571925

23. Papapetropoulos S, Ffrench-Mullen J, McCorquodale D, Qin Y, Pablo J, Mash DC. Multiregional gene expression profiling identifies MRPS6 as a possible candidate gene for Parkinson's disease. Gene Expr. 2006; 13: 205–15. doi: 10.3727/000000006783991827 17193926

24. Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, et al. PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease. Science translational medicine. 2010; 2: 52ra73. doi: 10.1126/scitranslmed.3001059 20926834

25. Ryan SD, Dolatabadi N, Chan SF, Zhang X, Akhtar MW, Parker J, et al. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1alpha transcription. Cell. 2013; 155: 1351–64. doi: 10.1016/j.cell.2013.11.009 24290359

26. Phani S, Gonye G, Iacovitti L. VTA neurons show a potentially protective transcriptional response to MPTP. Brain Res. 2010; 1343: 1–13. doi: 10.1016/j.brainres.2010.04.061 20462502

27. Miller RM, Callahan LM, Casaceli C, Chen L, Kiser GL, Chui B, et al. Dysregulation of gene expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse substantia nigra. J Neurosci. 2004; 24: 7445–54. doi: 10.1523/JNEUROSCI.4204-03.2004 15329391

28. Ju C, Gao J, Hou L, Wang L, Zhang F, Sun F, et al. Neuroprotective effect of chondroitin sulfate on SHSY5Y cells overexpressing wildtype or A53T mutant alphasynuclein. Molecular medicine reports. 2017; 16: 8721–8. doi: 10.3892/mmr.2017.7725 28990084

29. van Heesbeen HJ, Smidt MP. Entanglement of Genetics and Epigenetics in Parkinson's Disease. Front Neurosci. 2019; 13: 277. doi: 10.3389/fnins.2019.00277 30983962

30. Ekstrand MI, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007; 104: 1325–30. doi: 10.1073/pnas.0605208103 17227870

31. Bedard C, Wallman MJ, Pourcher E, Gould PV, Parent A, Parent M. Serotonin and dopamine striatal innervation in Parkinson's disease and Huntington's chorea. Parkinsonism & related disorders. 2011; 17: 593–8. doi: 10.1016/j.parkreldis.2011.05.012 21664855

32. Sossi V, de La Fuente-Fernandez R, Holden JE, Doudet DJ, McKenzie J, Stoessl AJ, et al. Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18 F-fluorodopa data. J Cereb Blood Flow Metab. 2002; 22: 232–9. doi: 10.1097/00004647-200202000-00011 11823721

33. Strecker RE, Sharp T, Brundin P, Zetterstrom T, Ungerstedt U, Bjorklund A. Autoregulation of dopamine release and metabolism by intrastriatal nigral grafts as revealed by intracerebral dialysis. Neuroscience. 1987; 22: 169–78. doi: 10.1016/0306-4522(87)90207-7 2819773

34. Galter D, Pernold K, Yoshitake T, Lindqvist E, Hoffer B, Kehr J, et al. MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease. Genes Brain Behav. 2010; 9: 173–81. doi: 10.1111/j.1601-183X.2009.00542.x 20002202

35. Varanese S, Birnbaum Z, Rossi R, Di Rocco A. Treatment of advanced Parkinson's disease. Parkinsons Dis. 2011; 2010: 480260. doi: 10.4061/2010/480260 21331376

36. Nair-Roberts RG, Chatelain-Badie SD, Benson E, White-Cooper H, Bolam JP, Ungless MA. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience. 2008; 152: 1024–31. doi: 10.1016/j.neuroscience.2008.01.046 18355970

37. Grunblatt E, Riederer P. Aldehyde dehydrogenase (ALDH) in Alzheimer's and Parkinson's disease. J Neural Transm (Vienna). 2016; 123: 83–90. doi: 10.1007/s00702-014-1320-1 25298080

38. Jinsmaa Y, Sharabi Y, Sullivan P, Isonaka R, Goldstein DS. 3,4-Dihydroxyphenylacetaldehyde-Induced Protein Modifications and Their Mitigation by N-Acetylcysteine. J Pharmacol Exp Ther. 2018; 366: 113–24. doi: 10.1124/jpet.118.248492 29700232

39. Jinsmaa Y, Isonaka R, Sharabi Y, Goldstein DS. 3,4-Dihydroxyphenylacetaldehyde Is More Efficient than Dopamine in Oligomerizing and Quinonizing alpha-Synuclein. J Pharmacol Exp Ther. 2020; 372: 157–65. doi: 10.1124/jpet.119.262246 31744850

40. Goldstein DS, Sullivan P, Holmes C, Miller GW, Alter S, Strong R, et al. Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease. J Neurochem. 2013; 126: 591–603. doi: 10.1111/jnc.12345 23786406

41. Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP, Hoekstra JG, et al. Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress. Neuron. 2015; 87: 371–81. doi: 10.1016/j.neuron.2015.06.034 26182419

42. Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol. 2010; 67: 715–25. doi: 10.1002/ana.21995 20517933

43. Brichta L, Shin W, Jackson-Lewis V, Blesa J, Yap EL, Walker Z, et al. Identification of neurodegenerative factors using translatome-regulatory network analysis. Nat Neurosci. 2015; 18: 1325–33. doi: 10.1038/nn.4070 26214373

44. Laguna A, Schintu N, Nobre A, Alvarsson A, Volakakis N, Jacobsen JK, et al. Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease. Nat Neurosci. 2015; 18: 826–35. doi: 10.1038/nn.4004 25915474

45. Doucet-Beaupre H, Gilbert C, Profes MS, Chabrat A, Pacelli C, Giguere N, et al. Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons. Proc Natl Acad Sci U S A. 2016; 113: E4387–96. doi: 10.1073/pnas.1520387113 27407143

46. Doucet-Beaupre H, Ang SL, Levesque M. Cell fate determination, neuronal maintenance and disease state: The emerging role of transcription factors Lmx1a and Lmx1b. FEBS Lett. 2015; 589: 3727–38. doi: 10.1016/j.febslet.2015.10.020 26526610

47. Mogi M, Kondo T, Mizuno Y, Nagatsu T. p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain. Neurosci Lett. 2007; 414: 94–7. doi: 10.1016/j.neulet.2006.12.003 17196747

48. O'Brien TW O'Brien BJ, Norman RA. Nuclear MRP genes and mitochondrial disease. Gene. 2005; 354: 147–51. doi: 10.1016/j.gene.2005.03.026 15908146

49. Liu G, Yu J, Ding J, Xie C, Sun L, Rudenko I, et al. Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. J Clin Invest. 2014; 124: 3032–46. doi: 10.1172/JCI72176 24865427

50. Panneton WM, Kumar VB, Gan Q, Burke WJ, Galvin JE. The neurotoxicity of DOPAL: behavioral and stereological evidence for its role in Parkinson disease pathogenesis. PLoS ONE. 2010; 5: e15251. doi: 10.1371/journal.pone.0015251 21179455

51. Moreno-Garcia A, Kun A, Calero O, Medina M, Calero M. An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration. Front Neurosci. 2018; 12: 464. doi: 10.3389/fnins.2018.00464 30026686

52. Pan T, Kondo S, Le W, Jankovic J. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease. Brain. 2008; 131: 1969–78. doi: 10.1093/brain/awm318 18187492

53. Gray DA, Woulfe J. Lipofuscin and aging: a matter of toxic waste. Sci Aging Knowledge Environ. 2005; 2005: re1. doi: 10.1126/sageke.2005.5.re1 15689603

54. Brewer GJ, Torricelli JR. Isolation and culture of adult neurons and neurospheres. Nat Protoc. 2007; 2: 1490–8. doi: 10.1038/nprot.2007.207 17545985

55. Saxena A, Wagatsuma A, Noro Y, Kuji T, Asaka-Oba A, Watahiki A, et al. Trehalose-enhanced isolation of neuronal sub-types from adult mouse brain. Biotechniques. 2012; 52: 381–5. doi: 10.2144/0000113878 22668417

56. Clayton DA, Shadel GS. Isolation of mitochondria from tissue culture cells. Cold Spring Harbor protocols. 2014; 2014: pdb prot080002. doi: 10.1101/pdb.prot080002 25275104

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2020 Číslo 6

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