Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease

Lusi Zhang^a,
Jie Deng^b,
Qian Pan^a,
Yan Zhan^a,
Jian-Bing Fan^{a, c},
Kun Zhang^{b
, ,},
Zhuohua Zhang^{a
, ,}

a.
Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China
b.
Department of Bioengineering, University of California at San Diego, California 92093, USA
c.
AnchorDx Corporation, International Bio-island, Guangzhou 510300, China

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Corresponding author: E-mail address: kzhang@bioeng.ucsd.edu (Kun Zhang); E-mail address: zhangzhuohua@sklmg.edu.cn (Zhuohua Zhang)

摘要

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Abstract: Parkinson disease (PD) is a progressive neurodegenerative movement disorder. Both environmental and genetic factors play important roles in PD etiology. A number of environmental toxins cause parkinsonism in human and animal models. Genetic studies of rare early onset familial PD cases resulted in identification of disease-linked mutations in multiple genes. Nevertheless, the potential interaction between environment and genetics in PD pathogenesis remains largely unknown. We hypothesized that environmental factors induce abnormal epigenetic regulation that is involved in the pathogenesis of both familial and sporadic PD. We determined the global methylation status of 80,000–110,000 CpG sites in each of the five sporadic PD patient brains and five age and postmodern interval matched control brains utilizing bisulfite padlock sequencing. Multiple genes involved in neurogenesis, particularly the ones in the Wnt signaling pathway, were hypermethylated in PD brains compared to their matched control brains. Consistent with the DNA methylation changes, marked reduction of protein expression was observed for four Wnt and neurogenesis related genes (FOXC1, NEURG2, SPRY1, and CTNNB1) in midbrain dopaminergic (DA) neurons of PD. The treatment of low concentration of 1-methyl-4-phenylpyridinium (MPP⁺) for cells resulted in downregulation of Wnt related genes. The study revealed an important link between the epigenetic disregulation of Wnt signaling and the pathogenesis and progression of PD.
- Epigenetic regulation /
- Neurodegenerative diseases /
- Environmental toxins /
- Neurogenesis

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参考文献(36)

[1]	Andersson, E., Jensen, J.B., Parmar, M. et al. Development of the mesencephalic dopaminergic neuron system is compromised in the absence of neurogenin 2 Development, 133 (2006),pp. 507-516
[2]	Bernheimer, H., Birkmayer, W., Hornykiewicz, O. et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations J. Neurol. Sci., 20 (1973),pp. 415-455
[3]	Calvanese, V., Lara, E., Kahn, A. et al. The role of epigenetics in aging and age-related diseases Ageing Res. Rev., 8 (2009),pp. 268-276
[4]	Castelo-Branco, G., Wagner, J., Rodriguez, F.J. et al. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a Proc. Natl. Acad. Sci. U. S. A., 100 (2003),pp. 12747-12752
[5]	Clevers, H. Wnt/beta-catenin signaling in development and disease Cell, 127 (2006),pp. 469-480
[6]	Deng, J., Shoemaker, R., Xie, B. et al. Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming Nat. Biotechnol., 27 (2009),pp. 353-360
[7]	Doi, A., Park, I.H., Wen, B. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts Nat. Genet., 41 (2009),pp. 1350-1353
[8]	Dunnett, S.B., Bjorklund, A. Prospects for new restorative and neuroprotective treatments in Parkinson's disease Nature, 399 (1999),pp. A32-A39
[9]	Faedo, A., Borello, U., Rubenstein, J.L. Repression of fgf signaling by sprouty1-2 regulates cortical patterning in two distinct regions and times J. Neurosci., 30 (2010),pp. 4015-4023
[10]	Goris, A., Williams-Gray, C.H., Foltynie, T. et al. Investigation of TGFβ2 as a candidate gene in multiple sclerosis and Parkinson's disease J. Neurol., 254 (2007),pp. 846-848
[11]	Hatano, T., Kubo, S., Sato, S. et al. Pathogenesis of familial Parkinson's disease: new insights based on monogenic forms of Parkinson's disease J. Neurochem., 111 (2009),pp. 1075-1093
[12]	Hatcher, J.M., Pennell, K.D., Miller, G.W. Parkinson's disease and pesticides: a toxicological perspective Trends Pharmacol. Sci., 29 (2008),pp. 322-329
[13]	Hoglinger, G.U., Rizk, P., Muriel, M.P. et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease Nat. Neurosci., 7 (2004),pp. 726-735
[14]	Irizarry, R.A., Ladd-Acosta, C., Wen, B. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores Nat. Genet., 41 (2009),pp. 178-186
[15]	Kele, J., Simplicio, N., Ferri, A.L. et al. Neurogenin 2 is required for the development of ventral midbrain dopaminergic neurons Development, 133 (2006),pp. 495-505
[16]	Kuwabara, T., Hsieh, J., Muotri, A. et al. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis Nat. Neurosci., 12 (2009),pp. 1097-1105
[17]	Le, W.D., Xu, P., Jankovic, J. et al. Nat. Genet., 33 (2003),pp. 85-89
[18]	Lees, A.J., Hardy, J., Revesz, T. Parkinson's disease Lancet, 373 (2009),pp. 2055-2066
[19]	Levecque, C., Elbaz, A., Clavel, J. et al. Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study Hum. Mol. Genet., 12 (2003),pp. 79-86
[20]	Lie, D.C., Colamarino, S.A., Song, H.J. et al. Wnt signalling regulates adult hippocampal neurogenesis Nature, 437 (2005),pp. 1370-1375
[21]	Masliah, E., Dumaop, W., Galasko, D. et al. Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes Epigenetics, 8 (2013),pp. 1030-1038
[22]	McMahon, A.P., Joyner, A.L., Bradley, A. et al. The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum Cell, 69 (1992),pp. 581-595
[23]	Moore, K., McKnight, A.J., Craig, D. et al. Epigenome-wide association study for Parkinson's disease Neuromolecular Med., 16 (2014),pp. 845-855
[24]	Nuber, S., Petrasch-Parwez, E., Winner, B. et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease J. Neurosci., 28 (2008),pp. 2471-2484
[25]	Park, G., Tan, J., Garcia, G. et al. Regulation of histone acetylation by autophagy in Parkinson disease J. Biol. Chem., 291 (2016),pp. 3531-3540
[26]	Prakash, N., Brodski, C., Naserke, T. et al. Development, 133 (2006),pp. 89-98
[27]	Siegenthaler, J.A., Ashique, A.M., Zarbalis, K. et al. Retinoic acid from the meninges regulates cortical neuron generation Cell, 139 (2009),pp. 597-609
[28]	Tan, E.K., Chung, H., Zhao, Y. et al. Genetic analysis of Nurr1 haplotypes in Parkinson's disease Neurosci. Lett., 347 (2003),pp. 139-142
[29]	Thomas, K.R., Capecchi, M.R. Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development Nature, 346 (1990),pp. 847-850
[30]	Verstraeten, A., Theuns, J., Van Broeckhoven, C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era Trends Genet., 31 (2015),pp. 140-149
[31]	Volta, M., Milnerwood, A.J., Farrer, M.J. Insights from late-onset familial parkinsonism on the pathogenesis of idiopathic Parkinson's disease Lancet Neurol., 14 (2015),pp. 1054-1064
[32]	Winner, B., Lie, D.C., Rockenstein, E. et al. Human wild-type alpha-synuclein impairs neurogenesis J. Neuropathol. Exp. Neurol., 63 (2004),pp. 1155-1166
[33]	Winner, B., Rockenstein, E., Lie, D.C. et al. Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis Neurobiol. Aging, 29 (2008),pp. 913-925
[34]	Zarbalis, K., Siegenthaler, J.A., Choe, Y. et al. Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development Proc. Natl. Acad. Sci. U. S. A., 104 (2007),pp. 14002-14007
[35]	Zhao, M., Momma, S., Delfani, K. et al. Evidence for neurogenesis in the adult mammalian substantia nigra Proc. Natl. Acad. Sci. U. S. A., 100 (2003),pp. 7925-7930
[36]	Zimprich, A., Grabowski, M., Asmus, F. et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome Nat. Genet., 29 (2001),pp. 66-69

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doi: 10.1016/j.jgg.2016.05.002

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Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease

Corresponding author: E-mail address: kzhang@bioeng.ucsd.edu (Kun Zhang); E-mail address: zhangzhuohua@sklmg.edu.cn (Zhuohua Zhang)

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doi: 10.1016/j.jgg.2016.05.002

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Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease

Corresponding author: E-mail address: kzhang@bioeng.ucsd.edu (Kun Zhang); E-mail address: zhangzhuohua@sklmg.edu.cn (Zhuohua Zhang)

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