Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease
Emerging evidence points to reactive glia as a pivotal factor in Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of basal ganglia injury, but whether astrocytes and microglia activation may exacerbate dopaminergic (DAergic) neuron demise and...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2011-02-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996110003669 |
| _version_ | 1818336640128516096 |
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| author | F. L'Episcopo C. Tirolo N. Testa S. Caniglia M.C. Morale C. Cossetti P. D'Adamo E. Zardini L. Andreoni A.E.C. Ihekwaba P.A. Serra D. Franciotta G. Martino S. Pluchino B. Marchetti |
| author_facet | F. L'Episcopo C. Tirolo N. Testa S. Caniglia M.C. Morale C. Cossetti P. D'Adamo E. Zardini L. Andreoni A.E.C. Ihekwaba P.A. Serra D. Franciotta G. Martino S. Pluchino B. Marchetti |
| author_sort | F. L'Episcopo |
| collection | DOAJ |
| description | Emerging evidence points to reactive glia as a pivotal factor in Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of basal ganglia injury, but whether astrocytes and microglia activation may exacerbate dopaminergic (DAergic) neuron demise and/or contribute to DAergic repair is presently the subject of much debate. Here, we have correlated the loss and recovery of the nigrostriatal DAergic functionality upon acute MPTP exposure with extensive gene expression analysis at the level of the ventral midbrain (VM) and striata (Str) and found a major upregulation of pro-inflammatory chemokines and wingless-type MMTV integration site1 (Wnt1), a key transcript involved in midbrain DAergic neurodevelopment. Wnt signaling components (including Frizzled-1 [Fzd-1] and β-catenin) were dynamically regulated during MPTP-induced DAergic degeneration and reactive glial activation. Activated astrocytes of the ventral midbrain were identified as candidate source of Wnt1 by in situ hybridization and real-time PCR in vitro. Blocking Wnt/Fzd signaling with Dickkopf-1 (Dkk1) counteracted astrocyte-induced neuroprotection against MPP+ toxicity in primary mesencephalic astrocyte–neuron cultures, in vitro. Moreover, astroglial-derived factors, including Wnt1, promoted neurogenesis and DAergic neurogenesis from adult midbrain stem/neuroprogenitor cells, in vitro. Conversely, lack of Wnt1 transcription in response to MPTP in middle-aged mice and failure of DAergic neurons to recover were reversed by pharmacological activation of Wnt/β-catenin signaling, in vivo, thus suggesting MPTP-reactive astrocytes in situ and Wnt1 as candidate components of neuroprotective/neurorescue pathways in MPTP-induced nigrostriatal DAergic plasticity. |
| first_indexed | 2024-12-13T14:42:32Z |
| format | Article |
| id | doaj.art-d2bb6587807e4aee9862227456093c5e |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T14:42:32Z |
| publishDate | 2011-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-d2bb6587807e4aee9862227456093c5e2022-12-21T23:41:34ZengElsevierNeurobiology of Disease1095-953X2011-02-01412508527Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's diseaseF. L'Episcopo0C. Tirolo1N. Testa2S. Caniglia3M.C. Morale4C. Cossetti5P. D'Adamo6E. Zardini7L. Andreoni8A.E.C. Ihekwaba9P.A. Serra10D. Franciotta11G. Martino12S. Pluchino13B. Marchetti14OASI Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN) ItalyOASI Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN) ItalyOASI Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN) ItalyOASI Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN) ItalyOASI Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN) ItalyCambridge Centre for Brain Repair Department of Clinical Neurosciences ED Adrian Building Forvie Site Robinson Way Cambridge CB2 0PY, UKMolecular Genetics of Mental Retardation Unit, San Raffaele Institute, Via Olgettina, 58 I-20132 Milan, ItalyNeuroimmunology Unit, National Neurological Instititute C. Mondino, Via Mondino 2, 27100 Pavia, ItalyNeuroimmunology Unit, National Neurological Instititute C. Mondino, Via Mondino 2, 27100 Pavia, ItalyCambridge Centre for Brain Repair Department of Clinical Neurosciences ED Adrian Building Forvie Site Robinson Way Cambridge CB2 0PY, UKDepartment of Pharmacology, University of Sassari, Medical School, Viale S. Pietro 43, 07100 Sassari, ItalyDepartment of Pharmacology, University of Sassari, Medical School, Viale S. Pietro 43, 07100 Sassari, ItalySan Raffaele Institute, Neuroimmunology Unit, DIBIT2 and Institute of Experimental Neurology (INSPE), Via Olgettina, 58 I-20132 Milan, ItalyCambridge Centre for Brain Repair Department of Clinical Neurosciences ED Adrian Building Forvie Site Robinson Way Cambridge CB2 0PY, UKOASI Institute for Research and Care on Mental Retardation and Brain Aging, Neuropharmacology Section, Via Conte Ruggero 73, 94018 Troina (EN) Italy; Department of Clinical and Molecular Biomedicine, Pharmacology Section, University of Catania, Viale A. Doria, 95125 Catania, Italy; Faculty of Pharmacy, University of Catania, Viale A. Doria, 95125 Catania, Italy; Corresponding author. Department of Experimental and Clinical Pharmacology and Faculty of Pharmacy, University of Catania, Viale A. Doria, 95125 Catania, Italy. Fax: +39 0935653327.Emerging evidence points to reactive glia as a pivotal factor in Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of basal ganglia injury, but whether astrocytes and microglia activation may exacerbate dopaminergic (DAergic) neuron demise and/or contribute to DAergic repair is presently the subject of much debate. Here, we have correlated the loss and recovery of the nigrostriatal DAergic functionality upon acute MPTP exposure with extensive gene expression analysis at the level of the ventral midbrain (VM) and striata (Str) and found a major upregulation of pro-inflammatory chemokines and wingless-type MMTV integration site1 (Wnt1), a key transcript involved in midbrain DAergic neurodevelopment. Wnt signaling components (including Frizzled-1 [Fzd-1] and β-catenin) were dynamically regulated during MPTP-induced DAergic degeneration and reactive glial activation. Activated astrocytes of the ventral midbrain were identified as candidate source of Wnt1 by in situ hybridization and real-time PCR in vitro. Blocking Wnt/Fzd signaling with Dickkopf-1 (Dkk1) counteracted astrocyte-induced neuroprotection against MPP+ toxicity in primary mesencephalic astrocyte–neuron cultures, in vitro. Moreover, astroglial-derived factors, including Wnt1, promoted neurogenesis and DAergic neurogenesis from adult midbrain stem/neuroprogenitor cells, in vitro. Conversely, lack of Wnt1 transcription in response to MPTP in middle-aged mice and failure of DAergic neurons to recover were reversed by pharmacological activation of Wnt/β-catenin signaling, in vivo, thus suggesting MPTP-reactive astrocytes in situ and Wnt1 as candidate components of neuroprotective/neurorescue pathways in MPTP-induced nigrostriatal DAergic plasticity.http://www.sciencedirect.com/science/article/pii/S0969996110003669AstrogliaNeurodegenerationNeuroinflammationNeuroprotectionParkinson disease |
| spellingShingle | F. L'Episcopo C. Tirolo N. Testa S. Caniglia M.C. Morale C. Cossetti P. D'Adamo E. Zardini L. Andreoni A.E.C. Ihekwaba P.A. Serra D. Franciotta G. Martino S. Pluchino B. Marchetti Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease Neurobiology of Disease Astroglia Neurodegeneration Neuroinflammation Neuroprotection Parkinson disease |
| title | Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease |
| title_full | Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease |
| title_fullStr | Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease |
| title_full_unstemmed | Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease |
| title_short | Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease |
| title_sort | reactive astrocytes and wnt β catenin signaling link nigrostriatal injury to repair in 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine model of parkinson s disease |
| topic | Astroglia Neurodegeneration Neuroinflammation Neuroprotection Parkinson disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996110003669 |
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