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

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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.

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Abbreviations

α-SYN:

α-Synuclein

DAergic:

Dopaminergic

DAT:

Dopamine transporter

GSK-3:

Glycogen synthase kinase-3

PP2A:

Protein phosphatase 2A

RA:

All-trans-retinoic acid

TH:

Tyrosine hydroxylase

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2012R1A1A3011420, 2015R1D1A1A01059598, and 2015M3A9E1028326 to H.J. Choi and 2011-0030928, 2011-0030049, and 2012-003338 to H. Seo).

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Authors and Affiliations

  1. College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, 13488, Republic of Korea

    Sasuk Kim, Juhee Lim, Yeojin Bang & Hyun Jin Choi

  2. Department of Bioengineering, College of Life Science, CHA University, Seongnam, 13488, Republic of Korea

    Jisook Moon

  3. Department of Pharmacology, School of Medicine, CHA University, Seongnam, 13488, Republic of Korea

    Min-Soo Kwon

  4. College of Pharmacy, Chungbuk National University, Cheongju, 28644, Republic of Korea

    Jin Tae Hong

  5. Department of Molecular and Life Sciences, Hanyang University, Ansan, 15588, Republic of Korea

    Jeha Jeon & Hyemyung Seo

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  1. Sasuk Kim
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Correspondence to Hyun Jin Choi.

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S Kim and J Lim contributed equally to this work.

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Kim, S., Lim, J., Bang, Y. et al. Alpha-Synuclein Suppresses Retinoic Acid-Induced Neuronal Differentiation by Targeting the Glycogen Synthase Kinase-3β/β-Catenin Signaling Pathway. Mol Neurobiol 55, 1607–1619 (2018). https://doi.org/10.1007/s12035-016-0370-9

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