Sirtuin 2 enhances dopaminergic differentiation via the AKT/GSK-3β/β-catenin pathway

Abstract Proper and efficient differentiation of dopaminergic (DA) neurons is essential for the cell-based dopamine replacement strategies that have become an attractive therapeutical option in Parkinson's disease, a disorder typically known for the degeneration of the nigral DA neurons. Here, we established that the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 2 (SIRT2) interacts with protein kinase B, and, via the glycogen synthase kinase 3β/β-catenin pathway, modulates the differentiation of DA neurons. Deletion of SIRT2 resulted in a decreased number of DA neurons in the substantia nigra and lower striatal fiber density in SIRT2 knock-out mice. Similarly, we found a decreased ratio of DA neurons in primary midbrain cultures treated with the SIRT2 inhibitor AK-7. Using protein kinase B and glycogen synthase kinase 3β inhibitors, we found that those molecules act downstream of SIRT2. Thus, SIRT2 acts as a novel regulator of the differentiation process of DA neurons, further supporting its potential as a therapeutic target in Parkinson's disease.