Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease.
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.
Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China.
Lusi
L
Zhang
Department of Bioengineering, University of California at San Diego, California 92093, USA.
Jie
J
Deng
Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China.
Qian
Q
Pan
Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China.
Yan
Y
Zhan
Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China; AnchorDx Corporation, International Bio-island, Guangzhou 510300, China.
Jian-Bing
JB
Fan
Department of Bioengineering, University of California at San Diego, California 92093, USA. Electronic address: kzhang@bioeng.ucsd.edu.
Kun
K
Zhang
Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China. Electronic address: zhangzhuohua@sklmg.edu.cn.
Zhuohua
Z
Zhang
D019175:DNA Methylation / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D017422:Sequence Analysis, DNA; D060449:Wnt Signaling Pathway / Q000235:genetics*
Environmental toxins; Epigenetic regulation; Neurodegenerative diseases; Neurogenesis