TET family proteins are dispensable for dopamine neurons in health and Parkinson’s disease pathology

Abstract

DNA undergoes demethylation via the oxidation of 5-methylcytosine (5mC), which is mediated by the Ten ElevenTranslocation (TET) family of proteins. Notably, 5hmC is highly enriched in the brain than other tissues, the levelof which is dynamically regulated during development, aging, and in brain disorders. In addition, accumulatingevidence 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 fordiverse types of neurons in health and brain disorders. In this study, by generating triple knockout (TKO) mice ofTET family proteins (TET1, 2, and 3) selectively in dopamine (DA) neurons, we investigated the functional rolesof TET proteins in the structure and the function of DA neurons, which are pivotal for voluntary movement,reward-related behaviors, and motivation. Here we unexpectedly show that triple knockout (TKO) of all three TETproteins in dopamine (DA) neurons did not lead to significant alterations of neuronal structure and function innormal and pathological conditions. Thus, contrary to the previous reports, TET family enzymes may bedispensable for the structure and function of dopamine neurons in health and Parkinson’s disease.