Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease
Lusi Zhang1, Jie Deng2, Qian Pan1
1Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China.
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.
Insights
Environmental toxins may trigger epigenetic changes, specifically DNA hypermethylation, in Parkinson disease (PD) brains. This epigenetic dysregulation affects Wnt signaling and neurogenesis genes, impacting PD pathogenesis and progression.
Area of Science:
- Neuroscience
- Genetics
- Epigenetics
Background:
- Parkinson disease (PD) is a progressive neurodegenerative disorder with known environmental and genetic links.
- The interplay between environmental factors and genetic predisposition in PD pathogenesis is not fully understood.
- Epigenetic dysregulation is a potential mechanism connecting environmental exposures to PD.
Purpose of the Study:
- To investigate the role of epigenetic alterations, specifically DNA methylation, in the pathogenesis of sporadic Parkinson disease.
- To explore the potential link between environmental factors, epigenetic changes, and the Wnt signaling pathway in PD.
Main Methods:
- Utilized bisulfite padlock sequencing to determine global CpG site methylation status in postmortem brains of PD patients and controls.
- Analyzed methylation patterns of genes involved in neurogenesis and the Wnt signaling pathway.
- Assessed protein expression of key Wnt and neurogenesis genes in midbrain dopaminergic neurons.
- Investigated the effect of MPP+ exposure on Wnt-related gene expression in cellular models.
Main Results:
- Identified significant hypermethylation of neurogenesis and Wnt signaling pathway genes in PD brains compared to controls.
- Observed reduced protein expression of Wnt and neurogenesis-related genes (FOXC1, NEURG2, SPRY1, CTNNB1) in dopaminergic neurons of PD patients.
- Demonstrated that MPP+ treatment downregulates Wnt-related genes, suggesting an environmental toxin link.
Conclusions:
- Epigenetic dysregulation, particularly DNA hypermethylation of Wnt signaling pathway genes, is implicated in Parkinson disease pathogenesis.
- Findings suggest a crucial link between environmental factors, epigenetic modifications, and the progression of PD.
- Wnt signaling pathway alterations may represent a key mechanism in PD development and advancement.
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