Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease
Abstract Kynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites,...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-84858-7 |
| _version_ | 1818430640657268736 |
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| author | Marie Katrin Bondulich Yilan Fan Yeojin Song Flaviano Giorgini Gillian P. Bates |
| author_facet | Marie Katrin Bondulich Yilan Fan Yeojin Song Flaviano Giorgini Gillian P. Bates |
| author_sort | Marie Katrin Bondulich |
| collection | DOAJ |
| description | Abstract Kynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD. |
| first_indexed | 2024-12-14T15:36:38Z |
| format | Article |
| id | doaj.art-3d08dbe362e24d8e84f312c876b96a6c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:36:38Z |
| publishDate | 2021-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3d08dbe362e24d8e84f312c876b96a6c2022-12-21T22:55:43ZengNature PortfolioScientific Reports2045-23222021-03-0111111810.1038/s41598-021-84858-7Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s diseaseMarie Katrin Bondulich0Yilan Fan1Yeojin Song2Flaviano Giorgini3Gillian P. Bates4Huntington’s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute At UCL, Queen Square Institute of Neurology, UCLHuntington’s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute At UCL, Queen Square Institute of Neurology, UCLHuntington’s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute At UCL, Queen Square Institute of Neurology, UCLDepartment of Genetics and Genome Biology, University of LeicesterHuntington’s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute At UCL, Queen Square Institute of Neurology, UCLAbstract Kynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD.https://doi.org/10.1038/s41598-021-84858-7 |
| spellingShingle | Marie Katrin Bondulich Yilan Fan Yeojin Song Flaviano Giorgini Gillian P. Bates Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease Scientific Reports |
| title | Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease |
| title_full | Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease |
| title_fullStr | Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease |
| title_full_unstemmed | Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease |
| title_short | Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease |
| title_sort | ablation of kynurenine 3 monooxygenase rescues plasma inflammatory cytokine levels in the r6 2 mouse model of huntington s disease |
| url | https://doi.org/10.1038/s41598-021-84858-7 |
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