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Medicine

基因-环境相互作用模型揭开帕金森病的隐形易感机制

Published: January 07, 2014
doi:
10.3791/50960
, , ,
1Center for Health Sciences,SRI International, 2Department of Chemistry and Biochemistry,University of California-Santa Cruz

Summary

脂氧酶 （LOX） 异酶可以产生可能增加或减少神经发炎和神经退化的产品。基因-环境相互作用研究可以识别LOX异位素特异性效应。使用1-甲基-4-苯-1，2，3，6-四氢皮里丁（MPTP）模型的硝基丙烯损伤在两个LOX异酶缺乏转基因线允许比较LOX异位素对多巴胺完整性和炎症的贡献。

Abstract

脂氧酶 （LOX） 活动与神经退行性疾病（如阿尔茨海默氏症）有关，但其对帕金森病 （PD） 发病机理的影响鲜为人知。基因-环境相互作用模型在揭开特定细胞通路毒性的影响方面有用，单凭遗传或毒性疾病模型是无法观察到的。要评估是否不同的LOX异位体有选择地有助于PD相关的神经退化，转基因（即 5-LOX和12/15-LOX缺乏）小鼠可以挑战一种毒素，模仿细胞损伤和死亡的紊乱。在这里，我们描述了使用神经毒素，1-甲基-4-苯-1，2，3，6-四氢胆碱（MPTP），它产生一个尼古斯特里亚病变，阐明LOX异位体对与PD相关的神经退化的独特贡献。在小鼠和非人类灵长类动物中使用MPTP是重新概括PD中硝基体损伤的既定证据。MPTP 诱发病变的程度通过 HPLC 对多巴胺及其代谢物的分析以及对酪氨酸羟基酶 （TH） 纹状体的半定量西方污点分析来衡量，该纹状体是多巴胺合成的限速酶。为了评估炎症标记，这可能证明LOX异酶选择性敏感性，胶质纤维酸性蛋白（GFAP）和Iba-1免疫组织化学在含有亚坦蒂亚尼格拉的大脑部分进行，GFAP西斑分析在纹状同源物上进行。这种实验方法可以为基因-环境相互作用提供新的见解，这些相互作用是尼古菌变性和PD的基础。

Introduction

使用基因-环境相互作用模型提供了一种方法，模仿可能影响特发性帕金森病（PD）的危险因素，并提供了一个机会来辨别机械学的见解，不太可能通过单独使用遗传或毒性系统来阐明1，2。在这里，我们说明了这一点，并描述了应用1-甲基-4-苯-1，2，3，6-四氢皮里丁（MPTP）小鼠模型的硝基质变性3，以更好地了解脂氧酶（LOX）异酶活性的神经发炎和毒性4的选择性。虽然LOX同位素的作用已被广泛评估在外周疾病5，6以及CNS疾病，包括中风7和阿尔茨海默病8，9，同位素家族的作用，在硝基质功能和退化相关的PD是不太清楚的，值得研究。MPTP神经毒素表现出乳胶病原体通路的优先退化，并重新概括了纹状多巴胺耗竭和尼格勒多巴胺细胞损失，这是PD患者10运动损伤的基础。虽然这种模型没有复制非运动和运动PD行为和坦率的α-核素阳性Lewy身体病理学的全干部， 它一直有助于阐明新的机械靶点，有助于尼古斯特菌损伤和早期转化测试，因为它是最好的特征非侵入性模型，可用于可靠地产生硝基细胞死亡伴随着纹状多巴胺损失11-15。广泛使用MPTP小鼠，其范式从急性，亚急性到慢性16-18，已允许标准化的给药，导致轻度至重度硝基层损伤19，20与激活不同的毒性机制，这取决于治疗方案18，21，22。因此，这允许一个”病变窗口”的目标，可能会导致增强或减少硝基质损伤取决于治疗剂或转基因模型使用23-25。

对于转化和发现生物学研究来说，同样必要的是用于评估损伤的技术以及这些方法提供的证据。对于 MPTP 鼠标模型， 评估病变的既定指标是测量纹状多巴胺语气的标记物，包括HPLC的多巴胺及其代谢物，以及西方斑点分析酪氨酸羟基酶（TH），多巴胺合成中的限速酶，以及利用西式污点分析和免疫化学4的胶质活化等退行事件指标。虽然这些是经典的神经化学、生化和组织学程序，但这些技术提供了关于黑鬼多巴明神经通路内损伤程度的关键和可重复读数，表明毒性机制，并被证明是了解PD退行性事件的宝贵工具。

Protocol

注：所有动物程序和动物护理方法均应经该机构的机构动物护理和使用委员会 （IACUC） 批准。此处描述的研究是按照 SRI 国际 IACUC 制定的准则进行的。 1. 收购和维护缺乏LOX的老鼠 在 7-8 周时购买 5-LOX 缺陷或 12/15-LOX 缺乏小鼠以及相应的菌株和性别匹配对照组，并在抵达后留出几天时间适应设施。 将老鼠保持在12小时的?…

Representative Results

这种毒素暴露模式可在MPTP与盐水注射动物中产生显著且可检测到的20%纹状多巴胺耗竭。需要注意的是，不同数量的MPTP可能会产生轻微的或多或少的病变：因此，为了提高精度，建议在使用新的大量神经毒素之前，在转基因中对野生型小鼠进行初步实验。使用轻度至中度病变，可以观察转基因的影响：严重的病变可能会产生”地板效应”，伤害过于严重，无法衰减或破坏，从而掩盖有害基因改变的影…

Discussion

这种基因-环境相互作用研究的设计使我们能够获得关于5-LOX同位素在硝基质通路中的双重性质的新信息。通过执行HPLC测量盐水或MPTP治疗后，缺乏5-LOX异丙胺及其野生类型的垃圾伴侣的转基因药物的纹状单胺，我们能够注意到，其缺乏似乎在有毒条件下是保护性的（图1），但在正常情况下，缺乏酶会降低纹状多巴胺水平，并可能有害。因此，我们能够证明，5-LOX同位素有助于纹状多巴?…

Disclosures

The authors have nothing to disclose.

Acknowledgements

这项工作由国家卫生研究院NIGMS 056062资助。

Materials

1-Methyl-4-phenyl-1,2,3,6-tetra-hydropyridine hydrochloride (MPTP-HCL) Sigma-Aldrich M0896 for PD modeling
4% Formaldehyde (paraformaldehyde) solution, phosphate-buffered (PFA) American MasterTech Scientific BUP0157 for immersion fixation
Perchloric acid ACS reagent, 70% (PCA) Sigma-Aldrich 244252 for HPLC acid extraction
Tris Base Sigma-Aldrich T1503 for tissue homogenization
Ethylenediaminotetraacetic acid disodium salt dihydrate (EDTA) Sigma-Aldrich E1644 for tissue homogenization
Protease inhibitor cocktail Sigma-Aldrich P8340 for tissue homogenization
Phosphatase inhibitor cocktail Sigma-Aldrich P5726 for tissue homogenization
Sodium Hydroxide (NaOH) Sigma-Aldrich S5881 for Lowry protein assay
Sucrose, molecular biology, ≥99.5% (GC)  Sigma-Aldrich S0389 for cryoprotection
Phosphate buffered saline, powder, pH 7.4 (for 0.01 M PBS) Sigma-Aldrich P3813 for IHC
BCA Protein Assay Kit Pierce/Thermo 23225 for protein determination
Novex 12% Tris-Glycine Mini Gels 1.0 mm, 12-well Invitrogen/Life Technologies EC60052BOX for SDS-PAGE
NuPAGE LDS Sample Buffer (4x) Invitrogen/Life Technologies NP0007 for SDS-PAGE
Novex Sharp Prestained Protein Standard  Invitrogen/Life Technologies LC5800 protein ladder
Glycine Sigma-Aldrich G7126 for SDS-PAGE
Sodium dodecyl sulfate, electrophoresis, 98.5% (SDS) Sigma-Aldrich L3771 for SDS-PAGE
Methyl Alcohol, Anhydrous, Reagent  American MasterTech Scientific SPM1057C methanol for transfer
Sodium chloride (NaCl), ACS reagent Sigma-Aldrich S9888 saline and buffers
Nonfat dry milk powder Carnation n/a for immunoblotting
Ponceau S solution in 5% acetic acid  Sigma-Aldrich P7170 for immunoblotting
Anti-Tyrosine Hydroxylase (TH), sheep polyclonal Chemicon/Millipore AB1542 for immunofluorescence 
Anti-Tyrosine Hydroxylase (TH), rabbit polyclonal Pel-Freez Biologicals P40101-0 for immunoblotting
Anti-β Actin, rabbit Sigma-Aldrich A2066 for immunoblotting
Anti-Glial Fibrillary Acidic Protein (GFAP), rabbit polyclonal Chemicon/Millipore AB5804 for immunofluorescence
Anti-Glial Fibrillary Acidic Protein (GFAP), mouse monoclonal Covance Inc. SMI-22R for immunoblotting
Tween-20 Sigma-Aldrich P1379 for immunoblotting
Goat Anti-Rabbit IgG (H+L), Peroxidase Conjugated  Fisher Scientific 31462 for immunofluorescence
goat anti-sheep, peroxidase conjugated Pierce/Thermo 31480 for immunofluorescence
goat anti-mouse, peroxidase conjugated Pierce/Thermo 31430 for immunofluorescence
SuperSignal West Pico Chemiluminescent Substrate Pierce/Thermo 34078 for immunoblotting
CL-XPosure Film 7 in x 9.5 in  Pierce/Thermo 34089 for immunoblotting
Restore Western Blot Stripping Buffer  Pierce/Thermo 21059 for immunoblotting
Citric acid monohydrate, ACS reagent, ≥99.0%  Sigma-Aldrich C1909 for IHC
Normal Donkey Serum Millipore S30-100ML for IHC
Polyvinylpyrrolidone (PVP) Sigma-Aldrich P5288 for IHC
Bovine Serum Albumin (BSA), lyophilized Sigma-Aldrich A3294 for IHC
Triton X-100 Fisher Scientific BP151-01 for IHC
Donkey anti-Rabbit IgG, Alexa Fluor 568-labeled  Invitrogen/Life Technologies A10042 for IHC
Donkey Anti-Sheep IgG (H+L), FITC  Jackson ImmunoResearch 713-095-147 for IHC
VECTASHIELD Hard-Set Mounting Medium with DAPI Vector Laboratories H-1500 for IHC
Normal Goat Serum Millipore S26-100ML for IHC
VECTASTAIN ABC Kit (Rabbit IgG )  Vector Laboratories PK-4001 for IHC; 10 µl each of solutions A and B per 1 ml PBS (per instructions )
DAB Peroxidase Substrate Kit, 3,3’-diaminobenzidine Vector Laboratories SK-4100 for IHC; per 5 ml cold ddH2O, add 2 drops buffer stock solution, 2 drops DAB, and 1 drop H2O2 (H2O2 is added immediately before use)
Hydrogen peroxide, 30% Sigma-Aldrich 216763 for quench step in IHC
Rabbit anti-Iba1 Biocare Medicals CP290A for IHC
Cresyl Violet Solution, Regular Strength  FD Neurotechnologies PS102-01  counterstain for Iba1 IHC
95% Ethanol, reagent alcohol Sigma-Aldrich R8382 dehydration for IHC
100% Absolute ethanol Mallinckrodt  7019-10 dehydration for IHC
Acetic acid Sigma-Aldrich A6283 destaining for IHC
Xylene Sigma-Aldrich 534056 clearing agent for IHC
DPX Mountant Sigma-Aldrich 06522 mounting medium for DAB IHC
O.C.T. Compound – Frozen Section Embedding Medium  American MasterTech Scientific EMOCTCS embeddium medium for cryostat cutting
Potassium permanganate Sigma-Aldrich 223468 to decontaminate DAB solution
Dopamine hydrochloride Sigma-Aldrich H8502 for HPLC
3,4-Dihydroxyphenylacetic acid (DOPAC) Sigma-Aldrich 850217 for HPLC
Homovanillic acid (HVA) Sigma-Aldrich H1252 for HPLC
Perchloric acid (PCA) – 70% Sigma-Aldrich 244252 for HPLC
Sodium dihydrogen phosphate monohydrate Sigma-Aldrich 71504 for HPLC
Citric acid monohydrate Sigma-Aldrich C1909 for HPLC
1-Octanesulfonic acid sodium salt (OSA) Sigma-Aldrich O8380 for HPLC
EDTA Sigma-Aldrich E1644 for HPLC
Acetonitrile EMD AX0145-1 for HPLC
HPLC-grade distilled deionized water (ddH2O) Millipore for HPLC
0.22 µm GSTF membrane Millipore for filtration
Corning Netwells Sigma-Aldrich CLS3477 polystyrene insert with polyester mesh bottom, for IHC
[header]
Ultrasonic cell disrupter (Soniprep 150) MSE MSE.41371.274
Microcentrifuge Eppendorf 5414R
ESA MD-150 reverse-phase column  ESA
HPLC Pump (Ultimate 3000) Dionex ISO-3100BM
HPLC Autosampler (Ultimate 3000) Dionex WPS-3000TSL
Electrochemical detector ESA Coulochem III
Guard Cell ESA 5020
Analytical Cell ESA 5011A
Chromeleon software Dionex
Eclipse E400 Nikon E400 light/fluorescent microscope
Disposable mouse cage Ancare N10HT
Microfilter top Ancare N10MBT
[header]
5-LOX- deficient mice The Jackson Laboratory 004155
12/15-LOX-deficient mice The Jackson Laboratory 002778
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Tags

Keywords: Gene-environment InteractionLipoxygenaseParkinson’s DiseaseMPTPNeurodegenerative DisordersNigrostriatal DegenerationDopamineTyrosine HydroxylaseInflammationGFAPIba-1
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Chou, V. P., Ko, N., Holman, T. R., Manning-Boğ, A. B. Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson’s Disease. J. Vis. Exp. (83), e50960, doi:10.3791/50960 (2014).
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