title: 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.
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.
authors.affiliation: Key Lab of Applied Pharmacology, Wei Fang Medical College, Weifang, 261053, China.|Department of Biochemistry, Wei Fang Medical College, Weifang, 261053, China.
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Department of Neurological Surgery, Wayne State University, Detroit, MI, USA. ezhao@med.wayne.edu.
authors.forename: Ethan Y
authors.initials: EY
authors.lastname: Zhao
authors.affiliation: Key Lab of Applied Pharmacology, Wei Fang Medical College, Weifang, 261053, China.
authors.forename: Wen-Xin
authors.initials: WX
authors.lastname: Zhuang
authors.affiliation: Department of Biochemistry, Wei Fang Medical College, Weifang, 261053, China.
authors.forename: Feng-Xiang
authors.initials: FX
authors.lastname: Sun
authors.affiliation: Key Lab of Applied Pharmacology, Wei Fang Medical College, Weifang, 261053, China.|Department of Pharmacology, Wei Fang Medical College, Weifang, 261053, China.
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Han
authors.affiliation: Key Lab of Applied Pharmacology, Wei Fang Medical College, Weifang, 261053, China.
authors.forename: Hui-Rong
authors.initials: HR
authors.lastname: Han
authors.affiliation: Department of Immunology, Wei Fang Medical College, Weifang, 261053, China.
authors.forename: Zhi-Juan
authors.initials: ZJ
authors.lastname: Lin
authors.affiliation: Key Lab of Applied Pharmacology, Wei Fang Medical College, Weifang, 261053, China.
authors.forename: Zhi-Fang
authors.initials: ZF
authors.lastname: Pan
authors.affiliation: Key Lab of Applied Pharmacology, Wei Fang Medical College, Weifang, 261053, China. qumeihua@hotmail.com.|Department of Pharmacology, Wei Fang Medical College, Weifang, 261053, China. qumeihua@hotmail.com.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Qu
authors.affiliation: Department of Neurosurgery, The Affiliated Hospital of Wei Fang Medical College, Weifang, 261031, Shandong, China. ezhao@med.wayne.edu.
authors.forename: Xian-Wei
authors.initials: XW
authors.lastname: Zeng
authors.affiliation: Department of Neurological Surgery, Wayne State University, Detroit, MI, USA.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002491:Central Nervous System Agents / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008246:Lysophospholipids / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology / Q000502:physiology; D009197:Myenteric Plexus / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D005904:Glial Fibrillary Acidic Protein; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; C032881:lysophosphatidic acid
keywords: Dopaminergic (DA); G protein-coupled receptors (GPCRs); Lysophosphatidic acid receptor 1 (LPA1); Parkinson’s disease (PD)