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LPA signaling is required for dopaminergic neuron development and is reduced through low expression of the LPA1 receptor in a 6-OHDA lesion model of Parkinson’s disease

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Abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid that activates at least five known G-protein-coupled receptors (GPCRs): LPA1–LPA5. The nervous system is a major locus for LPA1 expression. LPA has been shown to regulate neuronal proliferation, migration, and differentiation during central nervous system development as well as neuronal survival. Furthermore, deficient LPA signaling has been implicated in several neurological disorders including neuropathic pain and schizophrenia. Parkinson’s disease (PD) is a neurodegenerative movement disorder that results from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The specific molecular pathways that lead to DA neuron degeneration, however, are poorly understood. The influence of LPA in the differentiation of mesenchymal stem cells (MSCs) into DA neurons in vitro and LPA1 expression in a 6-hydroxydopamine (6-OHDA) lesion model of PD in vivo were examined in the present study. LPA induced neuronal differentiation in 80.2 % of the MSC population. These MSCs developed characteristic neuronal morphology and expressed the neuronal marker, neuron-specific enolase (NSE), while expression of the glial marker, glial fibrillary acidic protein (GFAP), was absent. Moreover, 27.6 % of differentiated MSCs were positive for tyrosine hydroxylase (TH), a marker for DA neurons. In the 6-OHDA PD rat model, LPA1 expression in the substantia nigra was significantly reduced compared to control. These results suggest LPA signaling via activation of LPA1 may be necessary for DA neuron development and survival. Furthermore, reduced LPA/LPA1 signaling may be involved in DA neuron degeneration thus contributing to the pathogenesis of PD.

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Abbreviations

LPA:

Lysophosphatidic acid

DA:

Dopamine

PD:

Parkinson’s disease

TH:

Tyrosine hydroxylase

MSCs:

Mesenchymal stem cells

GPCRs:

G protein-coupled receptors

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Acknowledgments

The authors would like to thank Prof. Xi Chen and Prof. Wenyu Fu for their valuable advice and helpful discussions. This work was supported through funding from the Shandong Provincial Natural Science Foundation, China (No.ZR2009CL047, No.ZR2009DM024, No.Y2008C129, No.ZR2009CM019, No.ZR2009DL013), the Scientific Research Foundation for Returned Scholars, and the Ministry of Education of China (2011, 43th). This research also received grant support from colleges and universities in Shandong Province through the Excellent Teachers International Training Cooperation Program.

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Authors and Affiliations

  1. Key Lab of Applied Pharmacology, Wei Fang Medical College, Weifang, 261053, China

    Xiao-yun Yang, Wen-xin Zhuang, Hai-lin Han, Hui-rong Han, Zhi-fang Pan & Mei-hua Qu

  2. Department of Biochemistry, Wei Fang Medical College, Weifang, 261053, China

    Xiao-yun Yang & Feng-xiang Sun

  3. Department of Neurological Surgery, Wayne State University, Detroit, MI, USA

    Ethan Y. Zhao & Yuchuan Ding

  4. Department of Pharmacology, Wei Fang Medical College, Weifang, 261053, China

    Hai-lin Han & Mei-hua Qu

  5. Department of Immunology, Wei Fang Medical College, Weifang, 261053, China

    Zhi-juan Lin

  6. Department of Neurosurgery, The Affiliated Hospital of Wei Fang Medical College, Weifang, 261031, Shandong, China

    Xian-wei Zeng

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  1. Xiao-yun Yang
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Correspondence to Ethan Y. Zhao.

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Yang, Xy., Zhao, E.Y., Zhuang, Wx. et al. LPA signaling is required for dopaminergic neuron development and is reduced through low expression of the LPA1 receptor in a 6-OHDA lesion model of Parkinson’s disease. Neurol Sci 36, 2027–2033 (2015). https://doi.org/10.1007/s10072-015-2295-x

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  • DOI: https://doi.org/10.1007/s10072-015-2295-x

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