Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein
Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein
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DOI：
10.1016/j.neuro.2013.04.002
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发表时间：
2013-07-01
期刊：
影响因子：
3.4
通讯作者：
Goudreau, John L.
中科院分区：
文献类型：
--
作者：
Benskey, Matthew;Lee, Ki Yong;Goudreau, John L.
帕金森病(PD)患者下丘脑结节漏斗状多巴胺(TIDA)神经元未受影响，而中脑黑质纹状体多巴胺(NSDA)神经元明显变性。急性暴露于神经毒物1-甲基-4-苯基-1，2，3，6-四氢吡啶后也观察到类似的易感性模式，并且TIDA神经元对MPTP的抵抗与Parkin和泛素羧基末端水解酶L-1的表达增加有关。在本研究中，我们观察了慢性MPTP暴露后，TIDA和NSDA神经元对MPTP急性给药的反应。给小鼠注射MPTP(20 mg/kg，皮下注射，每3.5天一次)或生理盐水(10毫升/公斤，皮下注射，每3.5天一次)。在21天的恢复期后，慢性生理盐水和MPTP治疗的小鼠再注射一次生理盐水(10ml/kg；S.C.)。或MPTP(20毫克/公斤；S.C.)24小时后处死动物。MPTP后，NSDA神经元表现出明显的轴突终末变性(表现为纹状体中DA、酪氨酸羟基酶(TH)和DA转运体浓度的降低)，黑质(SN)中的TH免疫反应(IR)神经元丢失，而TIDA神经元没有表现出明显的轴突终末病变或TH免疫阳性细胞体的丢失。NSDA神经元病理与黑质中Parkin和UCHL-1蛋白浓度的一过性下降有关，在慢性神经毒物暴露停止后21天，其浓度恢复到正常水平。TIDA神经元对MPTP毒性的抵抗与弓状核UCHL-1的一过性升高和Parkin的持续升高有关。TIDA神经元代表DA神经元群体，具有独特的固有能力来适应急性和慢性毒物给药，并持续升高神经保护蛋白PARKIN。增加Parkin和UCHL-1表达的能力与DA神经元对神经毒物暴露的抵抗力之间的相关性与这些特征与毒物相关神经变性潜在的不同易感性之间的功能联系是一致的。(C)2013 Elsevier Inc.保留所有权利。
Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methy1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined. Mice were treated with ten injections of either MPTP (20 mg/kg; s.c.; every 3.5 days) or saline vehicle (10 ml/kg; s.c.; every 3.5 days). Following a 21 day recovery period, chronic saline- and MPTP-treated mice received an additional injection of either saline (10 ml/kg; s.c.) or MPTP (20 mg/kg; s.c.) and were sacrificed 24 h later. NSDA neurons displayed significant axon terminal degeneration (as reflected by decreases in DA, tyrosine hydroxylase (TH) and DA transporter concentrations in the striatum) as well as loss of TH-immunoreactive (IR) neurons in the substantia nigra (SN) following MPTP, whereas TIDA neurons revealed no overt axon terminal pathology or loss of TH-IR cell bodies. NSDA neuronal pathology was associated with transient decreases in concentrations of parkin and UCHL-1 protein in the SN, which returned to normal levels by 21 days following cessation of chronic neurotoxicant exposure. Resistance of TIDA neurons to MPTP toxicity was correlated with a transient increase in UCHL-1 and a sustained elevation in parkin in the arcuate nucleus. TIDA neurons represent a DA neuron population with a unique and inherent ability to adapt to acute and chronic toxicant administration with a sustained elevation of the neuroprotective protein parkin. The correlation between the ability to increase parkin and UCHL-1 expression and the resistance of DA neurons to neurotoxicant exposure is consistent with a functional link between these features and an underlying differential susceptibility to toxicant-associated neurodegeneration. (C) 2013 Elsevier Inc. All rights reserved.