Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington's disease.
Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington's disease.
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DOI：
10.1038/s41598-021-84858-7
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发表时间：
2021-03-09
影响因子：
4.6
通讯作者：
Bates GP
中科院分区：
文献类型：
--
作者：
Bondulich MK;Fan Y;Song Y;Giorgini F;Bates GP
犬尿氨酸3-单加氧酶（KMO）调节犬尿氨酸通路（KP）中神经活性代谢物的水平，其失调与亨廷顿病（HD）的发病机制有关。KMO抑制导致相对于神经毒性代谢物的神经保护水平升高，并且在几种HD模型中发现可以改善疾病相关表型。在这里，我们将KMO敲除小鼠与R6/2 HD小鼠杂交，以检测KMO在大脑和外周的消耗的影响。R6/2小鼠外周组织中KP基因失调，KMO消融使其中一部分基因水平正常化。KP代谢产物也被评估，KMO消耗导致脑和外周神经保护尿酸水平升高，纹状体和皮层神经毒性3-羟基kunurenine水平显著降低。值得注意的是，在KMO缺失后，R6/2血浆中发现的促炎细胞因子TNFa、il - 1β、il - 4和il - 6水平升高。尽管这些改善KP失调和外周炎症，KMO消融对一些行为表型没有影响。因此，尽管R6/2小鼠的KMO基因抑制调节了一些代谢和炎症参数，但这些并不能转化为原发性疾病指标的改善，这可能与针对HD外周炎症的其他干预措施相关。
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.
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影响因子：
4.7
作者：
Doll DN;Rellick SL;Barr TL;Ren X;Simpkins JW
通讯作者：
Simpkins JW
影响因子：
5.8
作者：
Dixon LJ;Barnes M;Tang H;Pritchard MT;Nagy LE
通讯作者：
Nagy LE
DOI：
10.1073/pnas.1604453113
发表时间：
2016-05-10
影响因子：
11.1
作者：
Breda, Carlo;Sathyasaikumar, Korrapati V.;Giorgini, Flaviano
通讯作者：
Giorgini, Flaviano
影响因子：
4.8
作者：
Giorgini, Flaviano;Huang, Shao-Yi;Muchowski, Paul J.
通讯作者：
Muchowski, Paul J.
影响因子：
32.4
作者：
Gutiérrez-Vázquez C;Quintana FJ
通讯作者：
Quintana FJ