title: Alpha-Synuclein Suppresses Retinoic Acid-Induced Neuronal Differentiation by Targeting the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway.
abstract: Alpha-synuclein (α-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 α-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 α-SYN attenuated the RA-induced upregulation of tyrosine hydroxylase and dopamine transporter as well as neurite outgrowth in SH-SY5Y cells. In addition, GSK-3β inactivation and downstream β-catenin stabilization were associated with RA-induced differentiation, which was attenuated by α-SYN. Moreover, protein phosphatase 2A was positively regulated by α-SYN and was implicated in the α-SYN-mediated interference with RA signaling. The results obtained from SH-SY5Y cells were verified in primary cultures of mesencephalic DAergic neurons from A53T α-SYN transgenic mice, which represent high levels of α-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 α-SYN transgenic mice were significantly lower than those in littermate controls. The current results provide novel insight into the role of α-SYN in the regulation of neuronal differentiation, including DAergic neurons. Identifying the signaling pathway involved in the α-SYN-mediated dysregulation of neuronal differentiation could lead to a better understanding of the developmental processes underlying α-SYN-related pathologies and facilitate the discovery of specifically targeted therapeutics.
authors.affiliation: College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea.
authors.forename: Sasuk
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea.
authors.forename: Juhee
authors.initials: J
authors.lastname: Lim
authors.affiliation: College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea.
authors.forename: Yeojin
authors.initials: Y
authors.lastname: Bang
authors.affiliation: Department of Bioengineering, College of Life Science, CHA University, Seongnam, 13488, Republic of Korea.
authors.forename: Jisook
authors.initials: J
authors.lastname: Moon
authors.affiliation: Department of Pharmacology, School of Medicine, CHA University, Seongnam, 13488, Republic of Korea.
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, 28644, Republic of Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.affiliation: Department of Molecular and Life Sciences, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Jeha
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Department of Molecular and Life Sciences, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Hyemyung
authors.initials: H
authors.lastname: Seo
authors.affiliation: College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea. hjchoi3@cha.ac.kr.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D051844:alpha-Synuclein; D051176:beta Catenin; D014212:Tretinoin; D014446:Tyrosine 3-Monooxygenase; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Differentiation; Dopaminergic neuron; GSK-3β; Neurite outgrowth; α-Synuclein; β-Catenin