The role of parkin in the differential susceptibility of tuberoinfundibular and nigrostriatal dopamine neurons to acute toxicant exposure.
The role of parkin in the differential susceptibility of tuberoinfundibular and nigrostriatal dopamine neurons to acute toxicant exposure.
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DOI：
10.1016/j.neuro.2014.11.004
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发表时间：
2015-01
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 J.;Manfredsson, Fredric P.;Lookingland, Keith J.;Goudreau, John L.
帕金森病导致黑纹状体多巴胺（DA）神经元变性，而结节基底叶DA神经元不受影响。在暴露于1-甲基-4-苯基- 1,2,3,6 -四氢吡啶（MPTP）后观察到类似的模式。MPTP后结节眼底神经元恢复的机制与parkin蛋白上调有关。本研究利用重组腺相关病毒（rAAV）表达一种短发夹RNA （shRNA）靶向parkin，通过敲低结节状基底神经元中的parkin，来检测parkin是否介导MPTP后结节状基底神经元的恢复。敲除后，在mptp给药24小时后分析轴突末端DA和酪氨酸羟化酶（TH）浓度。在MPTP后24小时内，raav - shrna介导的内源性帕金蛋白敲低使结节基底神经元易受MPTP诱导的末端DA损失，但不受TH损失的影响。为了确定parkin上调的神经保护作用是否可以翻译到黑质纹状体神经元，将表达人类parkin的rAAV注射到小鼠黑质，并在mptp后24小时分析轴突末端DA和TH的浓度。过表达黑质parkin可阻止黑质纹状体神经元轴突终末和胞体TH的丢失，但对mptp后24h内终末DA的丢失无影响。这些数据表明，在急性MPTP给药后，帕金对于恢复结节基底神经元内终末DA浓度是必要的，并且帕金可以挽救MPTP诱导的黑纹状体神经元内TH的下降。
Parkinson Disease causes degeneration of nigrostriatal dopamine (DA) neurons, while tuberoinfundibular DA neurons remain unaffected. A similar pattern is observed following exposure to 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyradine (MPTP). The mechanism of tuberoinfundibular neuronal recovery from MPTP is associated with up-regulation of parkin protein. Here we tested if parkin mediates tuberoinfundibular neuronal recovery from MPTP by knocking-down parkin in tuberoinfundibular neurons using recombinant adeno-associated virus (rAAV), expressing a short hairpin RNA (shRNA) directed toward parkin. Following knockdown, axon terminal DA and tyrosine hydroxylase (TH) concentrations were analyzed 24 hours post-MPTP administration. rAAV-shRNA-mediated knockdown of endogenous parkin rendered tuberoinfundibular neurons susceptible to MPTP induced terminal DA loss, but not TH loss, within 24 hours post-MPTP. To determine if the neuroprotective benefits of parkin up-regulation could be translated to nigrostriatal neurons, rAAV expressing human parkin was injected into the substantia nigra of mice and axon terminal DA and TH concentrations were analyzed 24 hours post-MPTP. Nigral parkin over-expression prevented loss of TH in the axon terminals and soma of nigrostriatal neurons, but had no effect on terminal DA loss within 24h post-MPTP. These data show that parkin is necessary for the recovery of terminal DA concentrations within tuberoinfundibular neurons following acute MPTP administration, and parkin can rescue MPTP-induced decreases in TH within nigrostriatal neurons.
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影响因子：
14.8
作者：
Jackson-Lewis, Vernice;Przedborski, Serge
通讯作者：
Przedborski, Serge
影响因子：
3.3
作者：
Behrouz, B.;Drolet, R. E.;Goudreau, J. L.
通讯作者：
Goudreau, J. L.
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
影响因子：
11.2
作者：
LANGSTON, JW;FORNO, LS
通讯作者：
FORNO, LS
影响因子：
4.8
作者：
Blanchard-Fillion, B;Souza, JM;Ischiropoulos, H
通讯作者：
Ischiropoulos, H