Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression.
Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression.
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DOI：
10.1016/j.neuro.2012.02.001
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发表时间：
2012-06
期刊：
影响因子：
3.4
通讯作者：
Goudreau JL
中科院分区：
文献类型：
--
作者：
Benskey M;Behrouz B;Sunryd J;Pappas SS;Baek SH;Huebner M;Lookingland KJ;Goudreau JL
下丘脑结节漏斗部多巴胺 (TIDA) 神经元在帕金森病 (PD) 中不受影响，而中脑黑质纹状体多巴胺 (NSDA) 神经元显着变性。在急性和慢性 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 小鼠和鱼藤酮大鼠变性模型中观察到类似的易感性模式。目前尚不清楚 TIDA 神经元的抵抗对于这个独特的 DA 神经元子集来说是组成型还是诱导性细胞自主表型。在本研究中，采用单次注射 MPTP（20 mg/kg；皮下注射）进行治疗，以检查 TIDA 与 NSDA 神经元对急性损伤的反应。急性单剂量 MPTP 导致 TIDA 和 NSDA 神经元轴突末端 DA 最初丢失，仅 TIDA 神经元在治疗后 16 小时恢复。轴突末端 DA 的最初损失取决于 NSDA 神经元中的功能性多巴胺转运蛋白 (DAT)，但在 TIDA 神经元中不依赖于 DAT。与 NSDA 神经元相比，MPTP 的活性代谢物 1-甲基，4-苯基吡啶鎓 (MPP+) 在 TIDA 中达到更高的浓度，并且消除速度更慢，这表明毒物生物活性或分布受损不太可能解释观察到的 TIDA 神经元对 MPTP 暴露的抵抗。蛋白质合成的抑制阻止了 TIDA 神经元的恢复，这表明从损伤中恢复的能力取决于诱导的而不是组成性的细胞机制。此外，MPTP 后总酪氨酸羟化酶 (TH) 表达没有变化，表明 DA 合成中限速酶的上调并不能解释 TIDA 神经元的恢复。差异候选基因表达分析显示，在损伤恢复过程中，TIDA 神经元中 Parkin 和泛素羧基末端水解酶 L1 (UCH-L1) 表达（mRNA 和蛋白质）呈时间依赖性增加。 Parkin 表达也随着 MPTP 剂量的增加而增加。 Parkin 表达的增加特别发生在 TIDA 神经元内，表明这些神经元具有上调 Parkin 以响应 MPTP 诱导的损伤的内在能力。这些数据表明，TIDA 神经元具有应对有毒物质暴露和氧化应激增加的补偿机制，这种独特的 TIDA 神经元表型为剖析中枢 DA 神经元在毒性损伤后的自然抵抗机制提供了一个平台。
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 in acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and rotenone rat models of degeneration. It is not known if the resistance of TIDA neurons is a constitutive or induced cell-autonomous phenotype for this unique subset of DA neurons. In the present study, treatment with a single injection of MPTP (20 mg/kg; s.c.) was employed to examine the response of TIDA versus NSDA neurons to acute injury. An acute single dose of MPTP caused an initial loss of DA from axon terminals of both TIDA and NSDA neurons, with recovery occurring solely in TIDA neurons by 16 h post-treatment. Initial loss of DA from axon terminals was dependent on a functional dopamine transporter (DAT) in NSDA neurons but DAT-independent in TIDA neurons. The active metabolite of MPTP, 1-methyl, 4-phenylpyradinium (MPP+), reached higher concentration and was eliminated slower in TIDA compared to NSDA neurons, which indicates that impaired toxicant bioactivation or distribution is an unlikely explanation for the observed resistance of TIDA neurons to MPTP exposure. Inhibition of protein synthesis prevented TIDA neuron recovery, suggesting that the ability to recover from injury was dependent on an induced, rather than a constitutive cellular mechanism. Further, there were no changes in total tyrosine hydroxylase (TH) expression following MPTP, indicating that up-regulation of the rate-limiting enzyme in DA synthesis does not account for TIDA neuronal recovery. Differential candidate gene expression analysis revealed a time-dependent increase in parkin and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) expression (mRNA and protein) in TIDA neurons during recovery from injury. Parkin expression was also found to increase with incremental doses of MPTP. The increase in parkin expression occurred specifically within TIDA neurons, suggesting that these neurons have an intrinsic ability to up-regulate parkin in response to MPTP-induced injury. These data suggest that TIDA neurons have a compensatory mechanism to deal with toxicant exposure and increased oxidative stress, and this unique TIDA neuron phenotype provides a platform for dissecting the mechanisms involved in the natural resistance of central DA neurons following toxic insult.
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影响因子：
3.3
作者：
Behrouz, B.;Drolet, R. E.;Goudreau, J. L.
通讯作者：
Goudreau, J. L.
影响因子：
4.1
作者：
MATTHAEI, S;OLEFSKY, JM;KARNIELI, E
通讯作者：
KARNIELI, E
影响因子：
2.5
作者：
PERRY, TL;YONG, VW;WRIGHT, JM
通讯作者：
WRIGHT, JM
影响因子：
2.5
作者：
Gasser, Paul J.;Orchinik, Miles;Lowry, Christoprer A.
通讯作者：
Lowry, Christoprer A.
DOI：
10.1016/1055-8330(95)90015-2
发表时间：
1995-09-01
期刊：
NEURODEGENERATION
影响因子：
--
作者：
JACKSONLEWIS, V;JAKOWEC, M;PRZEDBORSKI, S
通讯作者：
PRZEDBORSKI, S