T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease
Abstract Background Parkinson’s disease (PD) is the second most prevalent movement disorder characterized by up to 80% loss of dopamine (DA) neurons and accumulation of Lewy body deposits composed of α-synuclein (α-syn). Accumulation of α-syn is associated with microglial activation, leading to a pr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01911-4 |
| _version_ | 1831634545652269056 |
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| author | Meena S. Subbarayan Charles Hudson Lauren D. Moss Kevin R. Nash Paula C. Bickford |
| author_facet | Meena S. Subbarayan Charles Hudson Lauren D. Moss Kevin R. Nash Paula C. Bickford |
| author_sort | Meena S. Subbarayan |
| collection | DOAJ |
| description | Abstract Background Parkinson’s disease (PD) is the second most prevalent movement disorder characterized by up to 80% loss of dopamine (DA) neurons and accumulation of Lewy body deposits composed of α-synuclein (α-syn). Accumulation of α-syn is associated with microglial activation, leading to a pro-inflammatory environment linked with the pathogenesis of PD. Along with microglia, CD4 and CD8 T cells are observed in SNpc. The contribution of T-cells to PD development remains unclear with studies demonstrating that they may mediate neurodegeneration or act in a neuroprotective manner. Methods Here, we assessed the contribution of T cells to PD neurodegeneration using an adeno-associated virus (AAV) coding human wild-type α-syn or GFP injected into the substantia nigra pars compacta (SNpc) in T cell deficient (athymic nude) and T cell competent (heterozygous) rats. The rats were behaviorally assessed with cylinder test to test paw bias. Following behavior testing, brains were collected and analyzed for markers of dopamine neuron, microglial activation, T cells, and α-syn expression. Results Injection of AAV9-α-syn unilaterally into the SN of T cell competent rats resulted in a significant paw bias in comparison to the controls at 60 days post-injection. Conversely, T cell-deficient rats injected with AAV9-α-syn showed no deficit in paw bias. As expected, injected T cell competent rats demonstrated a significant increase in microglial activation (MHCII staining) as well as significant dopaminergic neuron loss. In contrast, the T cell-deficient counterparts did not show a significant increase in microglial activation or significant neuron loss compared to the control animals. We also observed CD4 and CD8 T cells in SNpc following microglial MHCII expression and dopaminergic neuron loss. The time course of T cell entry correlates with upregulation of MHCII and the peak loss of TH+ cells in the SNpc. Conclusion These data demonstrate that T cell infiltration and microglial upregulation of MHCII are involved in α-synuclein-mediated DA neuron loss in this rat model of PD. |
| first_indexed | 2024-12-19T05:55:43Z |
| format | Article |
| id | doaj.art-5449f7022e694aeea53cadd1df8138a9 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-19T05:55:43Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-5449f7022e694aeea53cadd1df8138a92022-12-21T20:33:27ZengBMCJournal of Neuroinflammation1742-20942020-08-0117111610.1186/s12974-020-01911-4T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s diseaseMeena S. Subbarayan0Charles Hudson1Lauren D. Moss2Kevin R. Nash3Paula C. Bickford4Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South FloridaResearch Service, James A Haley Veterans HospitalCenter for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South FloridaDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South FloridaDepartment of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South FloridaAbstract Background Parkinson’s disease (PD) is the second most prevalent movement disorder characterized by up to 80% loss of dopamine (DA) neurons and accumulation of Lewy body deposits composed of α-synuclein (α-syn). Accumulation of α-syn is associated with microglial activation, leading to a pro-inflammatory environment linked with the pathogenesis of PD. Along with microglia, CD4 and CD8 T cells are observed in SNpc. The contribution of T-cells to PD development remains unclear with studies demonstrating that they may mediate neurodegeneration or act in a neuroprotective manner. Methods Here, we assessed the contribution of T cells to PD neurodegeneration using an adeno-associated virus (AAV) coding human wild-type α-syn or GFP injected into the substantia nigra pars compacta (SNpc) in T cell deficient (athymic nude) and T cell competent (heterozygous) rats. The rats were behaviorally assessed with cylinder test to test paw bias. Following behavior testing, brains were collected and analyzed for markers of dopamine neuron, microglial activation, T cells, and α-syn expression. Results Injection of AAV9-α-syn unilaterally into the SN of T cell competent rats resulted in a significant paw bias in comparison to the controls at 60 days post-injection. Conversely, T cell-deficient rats injected with AAV9-α-syn showed no deficit in paw bias. As expected, injected T cell competent rats demonstrated a significant increase in microglial activation (MHCII staining) as well as significant dopaminergic neuron loss. In contrast, the T cell-deficient counterparts did not show a significant increase in microglial activation or significant neuron loss compared to the control animals. We also observed CD4 and CD8 T cells in SNpc following microglial MHCII expression and dopaminergic neuron loss. The time course of T cell entry correlates with upregulation of MHCII and the peak loss of TH+ cells in the SNpc. Conclusion These data demonstrate that T cell infiltration and microglial upregulation of MHCII are involved in α-synuclein-mediated DA neuron loss in this rat model of PD.http://link.springer.com/article/10.1186/s12974-020-01911-4Parkinson’s diseaseα-synucleinT cellsDopamineMicrogliaNeuroinflammation |
| spellingShingle | Meena S. Subbarayan Charles Hudson Lauren D. Moss Kevin R. Nash Paula C. Bickford T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease Journal of Neuroinflammation Parkinson’s disease α-synuclein T cells Dopamine Microglia Neuroinflammation |
| title | T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease |
| title_full | T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease |
| title_fullStr | T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease |
| title_full_unstemmed | T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease |
| title_short | T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson’s disease |
| title_sort | t cell infiltration and upregulation of mhcii in microglia leads to accelerated neuronal loss in an α synuclein rat model of parkinson s disease |
| topic | Parkinson’s disease α-synuclein T cells Dopamine Microglia Neuroinflammation |
| url | http://link.springer.com/article/10.1186/s12974-020-01911-4 |
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