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T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson's disease.
J Neuroinflammation. 2020 Aug 15; 17(1):242.JN

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.

Authors+Show Affiliations

Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL-33612, USA. Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL-33612, USA.Research Service, James A Haley Veterans Hospital, 13000 Bruce B Downs Blvd, Tampa, FL-33612, USA.Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL-33612, USA.Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL-33612, USA.Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL-33612, USA. pbickfor@usf.edu. Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL-33612, USA. pbickfor@usf.edu. Research Service, James A Haley Veterans Hospital, 13000 Bruce B Downs Blvd, Tampa, FL-33612, USA. pbickfor@usf.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32799878

Citation

Subbarayan, Meena S., et al. "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, vol. 17, no. 1, 2020, p. 242.
Subbarayan MS, Hudson C, Moss LD, et al. T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson's disease. J Neuroinflammation. 2020;17(1):242.
Subbarayan, M. S., Hudson, C., Moss, L. D., Nash, K. R., & Bickford, P. C. (2020). 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, 17(1), 242. https://doi.org/10.1186/s12974-020-01911-4
Subbarayan MS, et al. T Cell Infiltration and Upregulation of MHCII in Microglia Leads to Accelerated Neuronal Loss in an Α-synuclein Rat Model of Parkinson's Disease. J Neuroinflammation. 2020 Aug 15;17(1):242. PubMed PMID: 32799878.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - T cell infiltration and upregulation of MHCII in microglia leads to accelerated neuronal loss in an α-synuclein rat model of Parkinson's disease. AU - Subbarayan,Meena S, AU - Hudson,Charles, AU - Moss,Lauren D, AU - Nash,Kevin R, AU - Bickford,Paula C, Y1 - 2020/08/15/ PY - 2020/02/26/received PY - 2020/07/27/accepted PY - 2020/8/18/entrez PY - 2020/8/18/pubmed PY - 2021/7/16/medline KW - Dopamine KW - Microglia KW - Neurodegenerative disorders KW - Neuroinflammation KW - Parkinson’s disease KW - T cells KW - α-synuclein SP - 242 EP - 242 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 17 IS - 1 N2 - 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/32799878/T_cell_infiltration_and_upregulation_of_MHCII_in_microglia_leads_to_accelerated_neuronal_loss_in_an_��_synuclein_rat_model_of_Parkinson's_disease_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01911-4 DB - PRIME DP - Unbound Medicine ER -