Epigenomic analysis of Parkinson's disease neurons identifies Tet2 loss as neuroprotective

Parkinson's disease brain neurons exhibit a widespread epigenetic dysregulation of enhancers that is linked to an upregulation of TET2. Inactivation of TET2 protects against nigral dopaminergic neuronal loss and neuroinflammation. Parkinson's disease (PD) pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively examine DNA methylation at enhancers, genome-wide, in neurons of patients with PD and of control individuals. We find a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. In particular, patients with PD exhibit an epigenetic and transcriptional upregulation ofTET2, a master-regulator of cytosine modification status.TET2depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons. Moreover,Tet2inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation.Tet2loss also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increasedTET2expression. DecreasedTet2activity is neuroprotective, in vivo, and may be a new therapeutic target for PD.