4.5 Article

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

Journal

NEUROLOGICAL SCIENCES
Volume 36, Issue 11, Pages 2027-2033

Publisher

SPRINGER-VERLAG ITALIA SRL
DOI: 10.1007/s10072-015-2295-x

Keywords

Lysophosphatidic acid receptor 1 (LPA(1)); Parkinson's disease (PD); Dopaminergic (DA); G protein-coupled receptors (GPCRs)

Funding

  1. Shandong Provincial Natural Science Foundation, China [ZR2009CL047, ZR2009DM024, Y2008C129, ZR2009CM019, ZR2009DL013]
  2. Scientific Research Foundation for Returned Scholars
  3. Ministry of Education of China
  4. colleges and universities in Shandong Province through the Excellent Teachers International Training Cooperation Program

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Lysophosphatidic acid (LPA) is a bioactive phospholipid that activates at least five known G-protein-coupled receptors (GPCRs): LPA(1)-LPA(5). The nervous system is a major locus for LPA(1) 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 LPA(1) 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, LPA(1) expression in the substantia nigra was significantly reduced compared to control. These results suggest LPA signaling via activation of LPA(1) may be necessary for DA neuron development and survival. Furthermore, reduced LPA/LPA(1) signaling may be involved in DA neuron degeneration thus contributing to the pathogenesis of PD.

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