Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's disease
Abstract Introduction Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons. Accumulating evidence has shown that activation of the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is an early and cardinal feature in PD...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-11-01
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| Series: | Brain and Behavior |
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| Online Access: | https://doi.org/10.1002/brb3.2784 |
| _version_ | 1811178166181429248 |
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| author | Chen Qiao Tao Dang Yan Zhou Yuan‐Zhang Zhou Rong Zhao Min Wang |
| author_facet | Chen Qiao Tao Dang Yan Zhou Yuan‐Zhang Zhou Rong Zhao Min Wang |
| author_sort | Chen Qiao |
| collection | DOAJ |
| description | Abstract Introduction Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons. Accumulating evidence has shown that activation of the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is an early and cardinal feature in PD progression. Nevertheless, little is known about the effect of NLRP3 in the substantia nigra pars compacta (SNc) on DA neurodegeneration. Methods and results In the present study, we constructed NLRP3 interference sequences wrapped by lentivirus (LV3‐siNlrp3) to facilitate NLRP3 knockdown in the SNc region by intracerebral stereotactic injection. Then, we explored the effects of NLPR3 knockdown on PD pathologies via behavioral monitoring, immunohistochemistry and western blot analysis in acute 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) mouse model. Moreover, we performed in vitro experiments to investigate the effect of microglial NLRP3 knockdown on DA neuron survival in the context of 1‐methyl‐4‐phenylpyridinium (MPP+) stimulation. Our results demonstrated that NLRP3 knockdown in the SNc region significantly improved MPTP‐induced dyskinesia, DA neuronal loss and microglia activation in vivo. Meanwhile, knockdown of microglial NLRP3 attenuated MPP+‐induced DA neuronal damage in an indirect coculture system in which neurons were cultured in microglial conditional medium. Cumulatively, these data reveal that microglial NLRP3 located in the SNc region is detrimental to DA neurons survival, and knockdown of microglial NLRP3 is a potential strategy to rescue DA neurons in the progression of PD. Conclusions This work demonstrates the role of NLRP3 in PD pathogenesis via microglia‐neuron communication, and sheds light on targeting microglial NLRP3 to develop disease‐modifying therapy for PD. |
| first_indexed | 2024-04-11T06:15:00Z |
| format | Article |
| id | doaj.art-1f569164f18945d7a931144b43b3f365 |
| institution | Directory Open Access Journal |
| issn | 2162-3279 |
| language | English |
| last_indexed | 2024-04-11T06:15:00Z |
| publishDate | 2022-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Brain and Behavior |
| spelling | doaj.art-1f569164f18945d7a931144b43b3f3652022-12-22T04:41:06ZengWileyBrain and Behavior2162-32792022-11-011211n/an/a10.1002/brb3.2784Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's diseaseChen Qiao0Tao Dang1Yan Zhou2Yuan‐Zhang Zhou3Rong Zhao4Min Wang5Department of Clinical Pharmacy The Affiliated Hospital of Jiangsu University, Jiangsu University Zhenjiang Jiangsu ChinaDepartment of Clinical Pharmacy The Affiliated Hospital of Jiangsu University, Jiangsu University Zhenjiang Jiangsu ChinaDepartment of Clinical Pharmacy Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Pharmacology Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Clinical Pharmacy The Affiliated Hospital of Jiangsu University, Jiangsu University Zhenjiang Jiangsu ChinaDepartment of Geriatrics Affiliated Brain Hospital of Nanjing Medical University Nanjing Jiangsu ChinaAbstract Introduction Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons. Accumulating evidence has shown that activation of the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is an early and cardinal feature in PD progression. Nevertheless, little is known about the effect of NLRP3 in the substantia nigra pars compacta (SNc) on DA neurodegeneration. Methods and results In the present study, we constructed NLRP3 interference sequences wrapped by lentivirus (LV3‐siNlrp3) to facilitate NLRP3 knockdown in the SNc region by intracerebral stereotactic injection. Then, we explored the effects of NLPR3 knockdown on PD pathologies via behavioral monitoring, immunohistochemistry and western blot analysis in acute 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) mouse model. Moreover, we performed in vitro experiments to investigate the effect of microglial NLRP3 knockdown on DA neuron survival in the context of 1‐methyl‐4‐phenylpyridinium (MPP+) stimulation. Our results demonstrated that NLRP3 knockdown in the SNc region significantly improved MPTP‐induced dyskinesia, DA neuronal loss and microglia activation in vivo. Meanwhile, knockdown of microglial NLRP3 attenuated MPP+‐induced DA neuronal damage in an indirect coculture system in which neurons were cultured in microglial conditional medium. Cumulatively, these data reveal that microglial NLRP3 located in the SNc region is detrimental to DA neurons survival, and knockdown of microglial NLRP3 is a potential strategy to rescue DA neurons in the progression of PD. Conclusions This work demonstrates the role of NLRP3 in PD pathogenesis via microglia‐neuron communication, and sheds light on targeting microglial NLRP3 to develop disease‐modifying therapy for PD.https://doi.org/10.1002/brb3.2784disease‐modifying therapydopaminergic neuronmicrogliaNLRP3Parkinson's disease |
| spellingShingle | Chen Qiao Tao Dang Yan Zhou Yuan‐Zhang Zhou Rong Zhao Min Wang Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's disease Brain and Behavior disease‐modifying therapy dopaminergic neuron microglia NLRP3 Parkinson's disease |
| title | Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's disease |
| title_full | Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's disease |
| title_fullStr | Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's disease |
| title_full_unstemmed | Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's disease |
| title_short | Targeting microglial NLRP3 in the SNc region as a promising disease‐modifying therapy for Parkinson's disease |
| title_sort | targeting microglial nlrp3 in the snc region as a promising disease modifying therapy for parkinson s disease |
| topic | disease‐modifying therapy dopaminergic neuron microglia NLRP3 Parkinson's disease |
| url | https://doi.org/10.1002/brb3.2784 |
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