Tet family proteins are dispensable for the structure and function of dopamine neurons in health and Parkinson's disease

Abstract

DNA undergoes demethylation via the oxidation of 5-methylcytosine (5mC), which is mediated by the Ten Eleven Translocation (TET) family of proteins. Notably, 5hmC is highly enriched in the brain than in other tissues, the level of which is dynamically regulated during development, aging, and in brain disorders. In addition, accumulating evidence has recently revealed that 5-hmC and TETs play a significant role in synaptic functions, anxiety, addiction, and cognition in several brain regions. Furthermore, TET enzymes have turned out to be essential for diverse types of neurons in health and brain disorders. In this study, by generating triple knockout (TKO) mice of TET family proteins (TET1, 2, and 3) selectively in dopamine (DA) neurons, we investigated the functional roles of TET proteins in the structure and the function of DA neurons, which are pivotal for voluntary movement, reward-related behaviors, and motivation. Immunohistochemistry analysis of dopaminergic neuronal markers revealed that DA neuron-specific TET1, 2, 3 TKO does not alter cellular structure and survival of DA neurons. Furthermore, whole-cell patch clamp recordings from substantia nigra pars compacta (SNc) DA neurons show that intrinsic properties and synaptic transmission of DA neurons are unchanged by disruption of TET family proteins. Thus, unexpectedly, cell type-specific KO of all three TET proteins did not lead to critical alterations of neuronal structure and function in DA neurons. Moreover, we revisited the pathophysiological importance of TET enzymes in Parkinson’s disease (PD) by utilizing both pharmacological and genetic mouse models of PD. Against our expectation, however, we found that PD pathology induced by two types of PD models is largely unaffected by disruption of TET family proteins, which suggests that the role of TET family proteins in the pathophysiology of PD can be weak. Thus, contrary to the previous reports, TET family enzymes may be dispensable for the structure and function of specific neurons in health and disease.