Alpha-Synuclein Suppresses Retinoic Acid-Induced Neuronal Differentiation by Targeting the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway

Alpha-synuclein (alpha-SYN) is expressed during neuronal development and is mainly involved in the modulation of synaptic transmission. Missense mutations and amplifications of this gene have been associated with the pathogenesis of Parkinson's disease. Here, we evaluate whether alpha-SYN plays a detrimental role in the phenotypic and morphological regulation of neurons. We also identify the underlying mechanisms of this process in all-trans-retinoic acid (RA)-induced differentiated SH-SY5Y cells, which represents dopaminergic (DAergic) phenotype. Our results indicate that overexpression of wild-type or mutant A53T alpha-SYN attenuated the RA-induced upregulation of tyrosine hydroxylase and dopamine transporter as well as neurite outgrowth in SH-SY5Y cells. In addition, GSK-3 beta inactivation and downstream beta-catenin stabilization were associated with RA-induced differentiation, which was attenuated by alpha-SYN. Moreover, protein phosphatase 2A was positively regulated by alpha-SYN and was implicated in the alpha-SYN-mediated interference with RA signaling. The results obtained from SH-SY5Y cells were verified in primary cultures of mesencephalic DAergic neurons from A53T alpha-SYN transgenic mice, which represent high levels of alpha-SYN and protein phosphatase 2A in the midbrain. The number and length of neurites in tyrosine hydroxylase-positive as well as Tau-positive cells from A53T alpha-SYN transgenic mice were significantly lower than those in littermate controls. The current results provide novel insight into the role of alpha-SYN in the regulation of neuronal differentiation, including DAergic neurons. Identifying the signaling pathway involved in the alpha-SYN-mediated dysregulation of neuronal differentiation could lead to a better understanding of the developmental processes underlying alpha-SYN-related pathologies and facilitate the discovery of specifically targeted therapeutics.