Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype
Abstract Background Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson’s disease (PD) and is also thought to be fundamentally involved in numerous immune functions. Thus, we assessed the role of LRRK2 in the context of the effects of the environmental toxicant, paraquat, t...
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1483-7 |
| _version_ | 1818516499315294208 |
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| author | Chris Rudyk Zach Dwyer Shawn Hayley CLINT membership |
| author_facet | Chris Rudyk Zach Dwyer Shawn Hayley CLINT membership |
| author_sort | Chris Rudyk |
| collection | DOAJ |
| description | Abstract Background Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson’s disease (PD) and is also thought to be fundamentally involved in numerous immune functions. Thus, we assessed the role of LRRK2 in the context of the effects of the environmental toxicant, paraquat, that has been implicated in PD and is known to affect inflammatory processes. Methods Male LRRK2 knockout (KO) and transgenic mice bearing the G2019S LRRK2 mutation (aged 6–8 months) or their littermate controls were exposed to paraquat (two times per week for 3 weeks), and sickness measures, motivational scores, and total home-cage activity levels were assessed. Following sacrifice, western blot and ELISA assays were performed to see whether or not LRRK2 expression would alter processes related to plasticity, immune response processes, or the stress response. Results Paraquat-induced signs of sickness, inflammation (elevated IL-6), and peripheral toxicity (e.g., organ weight) were completely prevented by LRRK2 knockout. In fact, LRRK2 knockout dramatically reduced not only signs of illness, but also the motivational (nest building) and home-cage activity deficits induced by paraquat. Although LRRK2 deficiency did not affect the striatal BDNF reduction that was provoked by paraquat, it did blunt the corticosterone elevation induced by paraquat, raising the possibility that LRRK2 may modulate aspects of the HPA stress axis. Accordingly, we found that transgenic mice bearing the G2019S LRRK2 mutation had elevated basal corticosterone, along with diminished hippocampal 5-HT1A levels. Conclusion We are the first to show the importance of LRRK2 in the peripheral neurotoxic and stressor-like effects of paraquat. These data are consistent with LRRK2 playing a role in the general inflammatory tone and stressor effects induced by environmental toxicant exposure. |
| first_indexed | 2024-12-11T00:43:05Z |
| format | Article |
| id | doaj.art-55f98499bde14386a634403ba984cd5b |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T00:43:05Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-55f98499bde14386a634403ba984cd5b2022-12-22T01:26:51ZengBMCJournal of Neuroinflammation1742-20942019-06-0116111310.1186/s12974-019-1483-7Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotypeChris Rudyk0Zach Dwyer1Shawn Hayley2CLINT membershipDepartment of Neuroscience, Carleton UniversityDepartment of Neuroscience, Carleton UniversityDepartment of Neuroscience, Carleton UniversityAbstract Background Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson’s disease (PD) and is also thought to be fundamentally involved in numerous immune functions. Thus, we assessed the role of LRRK2 in the context of the effects of the environmental toxicant, paraquat, that has been implicated in PD and is known to affect inflammatory processes. Methods Male LRRK2 knockout (KO) and transgenic mice bearing the G2019S LRRK2 mutation (aged 6–8 months) or their littermate controls were exposed to paraquat (two times per week for 3 weeks), and sickness measures, motivational scores, and total home-cage activity levels were assessed. Following sacrifice, western blot and ELISA assays were performed to see whether or not LRRK2 expression would alter processes related to plasticity, immune response processes, or the stress response. Results Paraquat-induced signs of sickness, inflammation (elevated IL-6), and peripheral toxicity (e.g., organ weight) were completely prevented by LRRK2 knockout. In fact, LRRK2 knockout dramatically reduced not only signs of illness, but also the motivational (nest building) and home-cage activity deficits induced by paraquat. Although LRRK2 deficiency did not affect the striatal BDNF reduction that was provoked by paraquat, it did blunt the corticosterone elevation induced by paraquat, raising the possibility that LRRK2 may modulate aspects of the HPA stress axis. Accordingly, we found that transgenic mice bearing the G2019S LRRK2 mutation had elevated basal corticosterone, along with diminished hippocampal 5-HT1A levels. Conclusion We are the first to show the importance of LRRK2 in the peripheral neurotoxic and stressor-like effects of paraquat. These data are consistent with LRRK2 playing a role in the general inflammatory tone and stressor effects induced by environmental toxicant exposure.http://link.springer.com/article/10.1186/s12974-019-1483-7Parkinson’sLRRK2InflammatoryMicrogliaCytokineToxicity |
| spellingShingle | Chris Rudyk Zach Dwyer Shawn Hayley CLINT membership Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype Journal of Neuroinflammation Parkinson’s LRRK2 Inflammatory Microglia Cytokine Toxicity |
| title | Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype |
| title_full | Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype |
| title_fullStr | Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype |
| title_full_unstemmed | Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype |
| title_short | Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype |
| title_sort | leucine rich repeat kinase 2 lrrk2 modulates paraquat induced inflammatory sickness and stress phenotype |
| topic | Parkinson’s LRRK2 Inflammatory Microglia Cytokine Toxicity |
| url | http://link.springer.com/article/10.1186/s12974-019-1483-7 |
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