Objective: Studies have shown that 5-hmC modification is the reverse reaction of DNA methylation, and that this process is regulated by TET family hydroxylases, but whether this modification plays a role in the pathophysiology of Parkinson’s disease (PD) is not clear. The present study opens a new avenue for PD prevention by targeting the cellular and biochemical pathways that decrease the TET2 level and 5hmC landscape.

Background: Environmental and genetic risk factors contribute to the pathogenesis of Parkinson’s disease (PD) and the associated midbrain dopaminergic neuron (mDA) loss, in which DNA methylation might play a critical role. However, the involvement of DNA hydroxymethylation and ten-eleven translocation (TET) enzymes in the onset and progression of PD remains unclear.

Method: To investigate the function of TET2 in PD, we test its expression in cellular and animal PD models and showed that upregulation of TET2 is possibly one of the underlying mechanisms of PD. Furthermore, we used hMeDIP-sequencing to reveal an aberrant epigenome 5-hydroxymethylcytosine (5-hmC) landscape in a PD cellular model.

Results: 5-hmC is associated with gene-rich regions in the genomes related to cell cycle, especially for Cdkn2A (cyclin dependent kinase inhibitor 2A). Moreover, we knockdown the expression of Tet2 through shRNA and found that knockdown Tet2 expression could suppress apoptosis and increased cell growth and survival in animal and cellular PD models.

Conclusion: In the present study, we reported the functions of TET2 proteins in the pathogenesis of PD and as novel epigenetic markers. And our study revealed the critical function of TET2 in PD development and directly links the CDKN2A activity-dependent epigenetic pathway to 5-hmC-mediated suppression of PD progression, suggesting a new strategy for epigenetic therapy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tet2-mediated-cdkn2a-dna-hydroxymethylation-in-dopaminergic-neuronal-injury-of-parkinsons-disease/