NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson's disease.
NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson's disease.
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DOI：
10.1371/journal.pone.0021907
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wood SA
中科院分区：
文献类型：
--
作者：
Cook AL;Vitale AM;Ravishankar S;Matigian N;Sutherland GT;Shan J;Sutharsan R;Perry C;Silburn PA;Mellick GD;Whitelaw ML;Wells CA;Mackay-Sim A;Wood SA
如果没有合适的细胞模型，特发性帕金森病的病因仍不清楚。我们最近报道了一种新的患者来源的细胞模型，该模型来自于嗅黏膜活检(称为嗅神经球源性(Hons)细胞)，该细胞以疾病特异性的方式表达功能和遗传差异。对患者和对照Hons细胞的转录转录分析发现，NRF2转录因子信号通路在帕金森病中差异表达最多。我们通过加入更多的细胞系来测试我们最初发现的稳健性，并证实来自患者的HONS细胞与来自健康对照捐赠者的培养相比，降低了谷胱甘肽水平和MTS[3-(4，5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium，[内盐]代谢减少了20%。我们还证实，患者Hons细胞处于氧化应激状态，这是由于过氧化氢的产生高于对照培养。在对照供体细胞中，siRNA介导的NRF2消融降低了总谷胱甘肽含量和MTS代谢，使帕金森病患者细胞中检测到的水平。相反，更重要的是，我们证明了在帕金森病Hons培养中激活NRF2通路使谷胱甘肽水平和MTS代谢恢复到对照水平。矛盾的是，转录分析发现，在L-苏处理的患者来源的HONS细胞中，与L-苏处理的对照组相比，在NRF2途径激活后的转录转录分析中差异表达的mRNAs的数量增加，即使他们的代谢恢复正常。我们还发现了PI3K/AKT信号通路的差异表达，但仅在治疗后表达。我们的结果证实了NRF2是帕金森病的潜在治疗靶点，并首次证明了NRF2功能可以在来自具有独特不同遗传背景的捐赠者的患者来源的细胞中诱导。然而，我们的结果也表明，帕金森病患者来源的细胞的反应并不像对照细胞那样协调。这可能是开发新疗法时的一个重要因素。
Without appropriate cellular models the etiology of idiopathic Parkinson's disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functional and genetic differences in a disease-specific manner. Transcriptomic analysis of Patient and Control hONS cells identified the NRF2 transcription factor signalling pathway as the most differentially expressed in Parkinson's disease. We tested the robustness of our initial findings by including additional cell lines and confirmed that hONS cells from Patients had 20% reductions in reduced glutathione levels and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] metabolism compared to cultures from healthy Control donors. We also confirmed that Patient hONS cells are in a state of oxidative stress due to higher production of H2O2 than Control cultures. siRNA-mediated ablation of NRF2 in Control donor cells decreased both total glutathione content and MTS metabolism to levels detected in cells from Parkinson's Disease patients. Conversely, and more importantly, we showed that activation of the NRF2 pathway in Parkinson's disease hONS cultures restored glutathione levels and MTS metabolism to Control levels. Paradoxically, transcriptomic analysis after NRF2 pathway activation revealed an increased number of differentially expressed mRNAs within the NRF2 pathway in L-SUL treated Patient-derived hONS cells compared to L-SUL treated Controls, even though their metabolism was restored to normal. We also identified differential expression of the PI3K/AKT signalling pathway, but only post-treatment. Our results confirmed NRF2 as a potential therapeutic target for Parkinson's disease and provided the first demonstration that NRF2 function was inducible in Patient-derived cells from donors with uniquely varied genetic backgrounds. However, our results also demonstrated that the response of PD patient-derived cells was not co-ordinated in the same way as in Control cells. This may be an important factor when developing new therapeutics.
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DOI：
10.1016/s1387-2656(05)11004-7
发表时间：
2005-01-01
期刊：
BIOTECHNOLOGY ANNUAL REVIEW, VOL 11
影响因子：
--
作者：
Berridge, MV;Herst, PM;Tan, AS
通讯作者：
Tan, AS
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
16.2
作者：
CORY, AH;OWEN, TC;CORY, JG
通讯作者：
CORY, JG
DOI：
10.1073/pnas.0813361106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Chen, Pei-Chun;Vargas, Marcelo R.;Johnson, Jeffrey A.
通讯作者：
Johnson, Jeffrey A.
影响因子：
4.9
作者：
Dick, F. D.;De Palma, G.;Felice, A.
通讯作者：
Felice, A.