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Conditional Haploinsufficiency of β-Catenin Aggravates Neuronal Damage in a Paraquat-Based Mouse Model of Parkinson Disease

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Abstract

The canonical Wnt pathway is critical for both the development and adulthood survival and homeostatic maintenance of the midbrain dopaminergic (DA) neurons. Expanding evidence has demonstrated that genetic factors associated with familial Parkinson disease (PD) deregulate this important pathway, suggesting that a disturbed canonical Wnt pathway is likely involved in PD pathogenesis; yet, the specific role of this pathway in sporadic PD remains unclear. In this study, we aimed to determine the effects of specific inhibition of the canonical pathway by hemizygous knockout of β-catenin, the obligatory component of the canonical Wnt pathway, on paraquat (PQ)-induced DA neuronal degeneration in the substantia nigra in vivo. We found that while hemizygous conditional knockout of β-catenin in DA neurons did not cause any significant TH+ neuronal loss in the substantia nigra at basal level, it triggered elevated oxidative stress at basal level and further enhanced PQ-induced oxidative damage and loss of TH+ neurons in the substantia nigra and axonal termini in the striatum that manifested as exacerbated motor deficits. These data support the notion that reduced Wnt/β-catenin signaling in sporadic PD likely contributes to DA neuronal loss through an enhanced oxidative stress-response pathway.

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Abbreviations

DA:

Dopaminergic

DAT:

Dopamine transporter

4-HNE:

4-Hydroxynonenal

JNKs:

c-Jun N-terminal kinases

KO:

Knockout

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PQ:

Paraquat

PD:

Parkinson disease

ROS:

Reactive oxygen species

SN:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

Tg:

Transgenic

VTA:

Ventral tegmental

References

  1. Jankovic J (2008) Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79(4):368–376. https://doi.org/10.1136/jnnp.2007.131045

    Article  CAS  PubMed  Google Scholar 

  2. Schapira AH (1997) Pathogenesis of Parkinson’s disease. Baillieres Clin Neurol 6(1):15–36

    CAS  PubMed  Google Scholar 

  3. Domingo A, Klein C (2018) Genetics of Parkinson disease. Handb Clin Neurol 147:211–227. https://doi.org/10.1016/B978-0-444-63233-3.00014-2

    Article  PubMed  Google Scholar 

  4. Dauer W, Przedborski S (2003) Parkinson's disease: mechanisms and models. Neuron 39(6):889–909

    Article  CAS  Google Scholar 

  5. Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S (2000) A meta-analysis of Parkinson’s disease and exposure to pesticides. Neurotoxicology 21(4):435–440

    CAS  PubMed  Google Scholar 

  6. Van Maele-Fabry G, Hoet P, Vilain F, Lison D (2012) Occupational exposure to pesticides and Parkinson’s disease: a systematic review and meta-analysis of cohort studies. Environ Int 46:30–43. https://doi.org/10.1016/j.envint.2012.05.004

    Article  CAS  PubMed  Google Scholar 

  7. Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC (1997) Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology 48(6):1583–1588

    Article  CAS  Google Scholar 

  8. Pezzoli G, Cereda E (2013) Exposure to pesticides or solvents and risk of Parkinson disease. Neurology 80(22):2035–2041. https://doi.org/10.1212/WNL.0b013e318294b3c8

    Article  CAS  PubMed  Google Scholar 

  9. Freire C, Koifman S (2012) Pesticide exposure and Parkinson’s disease: epidemiological evidence of association. Neurotoxicology 33(5):947–971. https://doi.org/10.1016/j.neuro.2012.05.011

    Article  CAS  PubMed  Google Scholar 

  10. Yan MH, Wang X, Zhu X (2013) Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 62:90–101. https://doi.org/10.1016/j.freeradbiomed.2012.11.014

    Article  CAS  PubMed  Google Scholar 

  11. Garcia-Velazquez L, Arias C (2017) The emerging role of Wnt signaling dysregulation in the understanding and modification of age-associated diseases. Ageing Res Rev 37:135–145. https://doi.org/10.1016/j.arr.2017.06.001

    Article  CAS  PubMed  Google Scholar 

  12. MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26. https://doi.org/10.1016/j.devcel.2009.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Castelo-Branco G, Wagner J, Rodriguez FJ, Kele J, Sousa K, Rawal N, Pasolli HA, Fuchs E et al (2003) Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc Natl Acad Sci U S A 100(22):12747–12752. https://doi.org/10.1073/pnas.1534900100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Joksimovic M, Awatramani R (2014) Wnt/beta-catenin signaling in midbrain dopaminergic neuron specification and neurogenesis. J Mol Cell Biol 6(1):27–33. https://doi.org/10.1093/jmcb/mjt043

    Article  CAS  PubMed  Google Scholar 

  15. Prakash N, Brodski C, Naserke T, Puelles E, Gogoi R, Hall A, Panhuysen M, Echevarria D et al (2006) A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo. Development 133(1):89–98. https://doi.org/10.1242/dev.02181

    Article  CAS  PubMed  Google Scholar 

  16. Fukusumi Y, Meier F, Gotz S, Matheus F, Irmler M, Beckervordersandforth R, Faus-Kessler T, Minina E et al (2015) Dickkopf 3 promotes the differentiation of a rostrolateral midbrain dopaminergic neuronal subset in vivo and from pluripotent stem cells in vitro in the mouse. J Neurosci 35(39):13385–13401. https://doi.org/10.1523/JNEUROSCI.1722-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Salasova A, Yokota C, Potesil D, Zdrahal Z, Bryja V, Arenas E (2017) A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway. Mol Neurodegener 12(1):54. https://doi.org/10.1186/s13024-017-0193-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Berwick DC, Harvey K (2012) LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Hum Mol Genet 21(22):4966–4979. https://doi.org/10.1093/hmg/dds342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Berwick DC, Javaheri B, Wetzel A, Hopkinson M, Nixon-Abell J, Granno S, Pitsillides AA, Harvey K (2017) Pathogenic LRRK2 variants are gain-of-function mutations that enhance LRRK2-mediated repression of beta-catenin signaling. Mol Neurodegener 12(1):9. https://doi.org/10.1186/s13024-017-0153-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eaton S (2008) Retromer retrieves wntless. Dev Cell 14(1):4–6. https://doi.org/10.1016/j.devcel.2007.12.014

    Article  CAS  PubMed  Google Scholar 

  21. Rawal N, Corti O, Sacchetti P, Ardilla-Osorio H, Sehat B, Brice A, Arenas E (2009) Parkin protects dopaminergic neurons from excessive Wnt/beta-catenin signaling. Biochem Biophys Res Commun 388(3):473–478. https://doi.org/10.1016/j.bbrc.2009.07.014

    Article  CAS  PubMed  Google Scholar 

  22. Hofmann JW, McBryan T, Adams PD, Sedivy JM (2014) The effects of aging on the expression of Wnt pathway genes in mouse tissues. Age 36(3):9618. https://doi.org/10.1007/s11357-014-9618-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bayod S, Felice P, Andres P, Rosa P, Camins A, Pallas M, Canudas AM (2015) Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice. Neurobiol Aging 36(2):720–729. https://doi.org/10.1016/j.neurobiolaging.2014.09.017

    Article  CAS  PubMed  Google Scholar 

  24. Zhang L, Deng J, Pan Q, Zhan Y, Fan JB, Zhang K, Zhang Z (2016) Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease. J Genet Genomics 43(10):587–592. https://doi.org/10.1016/j.jgg.2016.05.002

    Article  PubMed  Google Scholar 

  25. Brault V, Moore R, Kutsch S, Ishibashi M, Rowitch DH, McMahon AP, Sommer L, Boussadia O et al (2001) Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128(8):1253–1264

    CAS  PubMed  Google Scholar 

  26. Wang W, Wang X, Fujioka H, Hoppel C, Whone AL, Caldwell MA, Cullen PJ, Liu J et al (2016) Parkinson’s disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. Nat Med 22(1):54–63. https://doi.org/10.1038/nm.3983

    Article  CAS  PubMed  Google Scholar 

  27. Jiang S, Nandy P, Wang W, Ma X, Hsia J, Wang C, Wang Z, Niu M et al (2018) Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex. Mol Neurodegener 13(1):5. https://doi.org/10.1186/s13024-018-0238-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, Yamaguchi H, Sakumi K, Yamakawa Y et al (2009) Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS One 4(9):e7247. https://doi.org/10.1371/journal.pone.0007247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dai TL, Zhang C, Peng F, Niu XY, Hu L, Zhang Q, Huang Y, Chen L et al (2014) Depletion of canonical Wnt signaling components has a neuroprotective effect on midbrain dopaminergic neurons in an MPTP-induced mouse model of Parkinson’s disease. Exp Ther Med 8(2):384–390. https://doi.org/10.3892/etm.2014.1745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823(1–2):1–10

    Article  CAS  Google Scholar 

  31. Selley ML (1998) (E)-4-hydroxy-2-nonenal may be involved in the pathogenesis of Parkinson’s disease. Free Radic Biol Med 25(2):169–174

    Article  CAS  Google Scholar 

  32. McCormack AL, Atienza JG, Johnston LC, Andersen JK, Vu S, Di Monte DA (2005) Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. J Neurochemy 93(4):1030–1037. https://doi.org/10.1111/j.1471-4159.2005.03088.x

    Article  CAS  Google Scholar 

  33. Choi WS, Abel G, Klintworth H, Flavell RA, Xia Z (2010) JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death. J Neuropathol Exp Neurol 69(5):511–520. https://doi.org/10.1097/NEN.0b013e3181db8100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P, Flavell RA (2004) JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 101(2):665–670. https://doi.org/10.1073/pnas.0307453101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhao F, Wang W, Wang C, Siedlak SL, Fujioka H, Tang B, Zhu X (2017) Mfn2 protects dopaminergic neurons exposed to paraquat both in vitro and in vivo: implications for idiopathic Parkinson’s disease. Biochim Biophys Acta 1863(6):1359–1370. https://doi.org/10.1016/j.bbadis.2017.02.016

    Article  CAS  PubMed Central  Google Scholar 

  36. L'Episcopo F, Tirolo C, Testa N, Caniglia S, Morale MC, Cossetti C, D'Adamo P, Zardini E et al (2011) Reactive astrocytes and Wnt/beta-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neurobiol Dis 41(2):508–527. https://doi.org/10.1016/j.nbd.2010.10.023

    Article  CAS  PubMed  Google Scholar 

  37. L'Episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, Pluchino S, Marchetti B (2011) A Wnt1 regulated Frizzled-1/beta-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener 6:49. https://doi.org/10.1186/1750-1326-6-49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dun Y, Li G, Yang Y, Xiong Z, Feng M, Wang M, Zhang Y, Xiang J et al (2012) Inhibition of the canonical Wnt pathway by Dickkopf-1 contributes to the neurodegeneration in 6-OHDA-lesioned rats. Neurosci Lett 525(2):83–88. https://doi.org/10.1016/j.neulet.2012.07.030

    Article  CAS  PubMed  Google Scholar 

  39. Gollamudi S, Johri A, Calingasan NY, Yang L, Elemento O, Beal MF (2012) Concordant signaling pathways produced by pesticide exposure in mice correspond to pathways identified in human Parkinson’s disease. PLoS One 7(5):e36191. https://doi.org/10.1371/journal.pone.0036191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wei L, Ding L, Mo MS, Lei M, Zhang L, Chen K, Xu P (2015) Wnt3a protects SH-SY5Y cells against 6-hydroxydopamine toxicity by restoration of mitochondria function. Transl Neurodegener 4:11. https://doi.org/10.1186/s40035-015-0033-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wei L, Sun C, Lei M, Li G, Yi L, Luo F, Li Y, Ding L et al (2013) Activation of Wnt/beta-catenin pathway by exogenous Wnt1 protects SH-SY5Y cells against 6-hydroxydopamine toxicity. J Mol Neurosci 49(1):105–115. https://doi.org/10.1007/s12031-012-9900-8

    Article  CAS  PubMed  Google Scholar 

  42. Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308(5725):1181–1184. https://doi.org/10.1126/science.1109083

    Article  CAS  PubMed  Google Scholar 

  43. Lento W, Ito T, Zhao C, Harris JR, Huang W, Jiang C, Owzar K, Piryani S et al (2014) Loss of beta-catenin triggers oxidative stress and impairs hematopoietic regeneration. Genes Dev 28(9):995–1004. https://doi.org/10.1101/gad.231944.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu P, Su J, Song X, Wang S (2017) Activation of nuclear beta-catenin/c-Myc axis promotes oxidative stress injury in streptozotocin-induced diabetic cardiomyopathy. Biochem Biophys Res Commun 493(4):1573–1580. https://doi.org/10.1016/j.bbrc.2017.10.027

    Article  CAS  PubMed  Google Scholar 

  45. Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE (2015) Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol 25(18):2349–2360. https://doi.org/10.1016/j.cub.2015.07.050

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was partly supported by the National Institute of Health [grant number NS083498 (to X. Zhu)], the Dr. Robert M. Kohrman Memorial Fund (to X. Zhu), the National Natural Science Foundation of China [No. 81430023 (to B. Tang)], the National Key Plan for Scientific Research and Development of China [No. 2016YFC1306000 (to B. Tang)], and the NSFC-NIH joint program [No. 81361120404 (to B. Tang)].

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Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA

    Fanpeng Zhao, Sandra L. Siedlak, Sandy L. Torres & Xiongwei Zhu

  2. Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya road, Changsha, 410008, Hunan, People’s Republic of China

    Qian Xu & Beisha Tang

  3. National Clinical Research Center for Geriatric Medicine, Changsha, Hunan, People’s Republic of China

    Beisha Tang

  4. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, People’s Republic of China

    Beisha Tang

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  1. Fanpeng Zhao
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  4. Qian Xu
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  5. Beisha Tang
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Contributions

FZ designed/carried out experiments, collected data and wrote the manuscript, SLS, SLR QX, BT contributed to interpretation of results and provided feedback on the manuscript. BT and XZ conceived the project. XZ directed the project, interpret results and wrote the manuscript. All authors had final approval of the submitted version.

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Correspondence to Beisha Tang or Xiongwei Zhu.

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Zhao, F., Siedlak, S.L., Torres, S.L. et al. Conditional Haploinsufficiency of β-Catenin Aggravates Neuronal Damage in a Paraquat-Based Mouse Model of Parkinson Disease. Mol Neurobiol 56, 5157–5166 (2019). https://doi.org/10.1007/s12035-018-1431-z

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