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Protein Phosphatase 2A is Involved in the Tyrosine Hydroxylase Phosphorylation Regulated by α-Synuclein

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Abstract

α-Synuclein (α-Syn) plays a crucial role in the pathophysiology of Parkinson’s disease (PD), the degeneration of dopaminergic neurons. Previous studies have shown that α-Syn regulates dopamine synthesis by binding to and inhibiting tyrosine hydroxylase (TH). In neurons, protein phosphatases (PPs) play a prominent role in directing signaling toward survival or degeneration. This study was to re-evaluate whether α-Syn could regulate the tyrosine hydroxylase phosphorylation by protein phosphatase-2A (PP2A) in dopaminergic MN9D cells and cortex neurons. Our data demonstrated for the first time that α-Syn stimulates PP2A activity and reduces phosphorylation of TH through regulating the methylation of PP2A in dopaminergic MN9D cells and primary cortex neurons. Increased PP2A activity and reduced phosphorylation of PP2A at Y307 (inactive form of PP2A) were observed in α-Syn overexpression dopaminergic cells (Syn) and primary cortex neurons, and the TH phosphorylation relieved by enhancing PP2A methylation in Syn group could be abated by using PP inhibitors, okadaic acid (OKA). OKA could reduce the cell damage and cell apoptosis induced by α-Syn. Thus our findings may provide an insight into the complicated pathogenesis of PD as well as some clues to the development of novel therapeutic strategies targeting at PP2A.

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Acknowledgments

This work was supported by Grants from the National Basic Research Program of China (2011CB504103, 2012CB722407). The authors are Grateful for support from Key Laboratory for Neurodegenerative Disease of the Ministry of Education (2011SJBX03) and Beijing Center of Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders (2011SJZS02).

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Authors and Affiliations

  1. Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100050, China

    Gao Hua & Zhang Yazhuo

  2. The Affiliated Hospital of Medical College, Qingdao University, Qingdao, 266003, China

    Lan Xiaolei

  3. Beijing Institute for Neuroscience, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders—State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing, 100069, China

    Yang Weiwei, Wang Hao, Zhu Yuangang, Liu Dongmei & Yang Hui

Authors
  1. Gao Hua
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  2. Lan Xiaolei
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  3. Yang Weiwei
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  4. Wang Hao
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  5. Zhu Yuangang
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Correspondence to Zhang Yazhuo or Yang Hui.

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Gao Hua and Lan Xiaolei have contributed equally to this work.

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11064_2014_1477_MOESM1_ESM.tif

Supplementary 1 α-synuclein didn’t alter the protein level of AADC or MAO. A: The AADC protein level was measured by western blot. There was no statistical difference of AADC in Syn group or Sh-Syn group. B: Monoamine oxidase plays an essential role in the catabolism of neurotransmitter amines in central and peripheral tissues. There was no statistical difference of MAO (TIFF 511 kb)

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Hua, G., Xiaolei, L., Weiwei, Y. et al. Protein Phosphatase 2A is Involved in the Tyrosine Hydroxylase Phosphorylation Regulated by α-Synuclein. Neurochem Res 40, 428–437 (2015). https://doi.org/10.1007/s11064-014-1477-x

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  • DOI: https://doi.org/10.1007/s11064-014-1477-x

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