FosB and ΔFosB expression in brain regions containing differentially susceptible dopamine neurons following acute neurotoxicant exposure.
FosB and ΔFosB expression in brain regions containing differentially susceptible dopamine neurons following acute neurotoxicant exposure.
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DOI：
10.1016/j.brainres.2016.08.030
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发表时间：
2016-10-15
期刊：
影响因子：
2.9
通讯作者：
Lookingland KJ
中科院分区：
文献类型：
--
作者：
Patterson JR;Kim EJ;Goudreau JL;Lookingland KJ
帕金森病（PD）的特征在于进行性神经元变性，特别是黑质纹状体多巴胺（NSDA）神经元和随之而来的运动缺陷。在小鼠和非人灵长类动物中，NSDA神经元在暴露于神经毒物1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）后优先退化。与此相反，PD中的DA能神经元似乎不受影响，并在急性MPTP压迫诱导的损伤后恢复。TIDA神经元的恢复依赖于从头蛋白质合成，并与parkin mRNA和蛋白质表达的增加呈正相关。抑制parkin上调使TIDA神经元在MPTP暴露后易变性。除了parkin，其他潜在的保护蛋白可能是差异调节TIDA和NSDA神经元神经毒素暴露后。帕金和其他神经保护通路基因的潜在转录因子的调节是令人感兴趣的，因为它们可以为PD疾病修饰疗法提供新的靶点。因此，我们试图确定急性MPTP暴露后小鼠TIDA和NSDA神经元中AP-1转录因子c-Fos、c-Jun、FosB、ΔFosB和JunD的表达是否存在时间依赖性差异。我们观察到FosB和ΔFosB的表达在含有TIDA的脑区中增加，但在含有NSDA神经元的脑区中不增加。此外，ΔFosB的核表达和长期表达与其作为可能影响parkin转录的转录因子的作用一致，这可能是TIDA神经元从导致NSDA神经元变性的损伤中恢复的独特能力的基础。
Parkinson disease (PD) is characterized by progressive neuronal degeneration, in particular nigrostriatal dopamine (NSDA) neurons and consequent deficits in movement. In mice and non-human primates, NSDA neurons preferentially degenerate following exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tuberoinfundibular (TI) DA neurons, in contrast, appear to be unaffected in PD and recover following acute MPTP exposure-induced injury. The recovery of the TIDA neurons is dependent on de novo protein synthesis and positively correlated with an increase in parkin mRNA and protein expression. Inhibition of parkin upregulation renders TIDA neurons susceptible to degeneration following MPTP exposure. In addition to parkin, other potentially protective proteins are likely to be differentially regulated in TIDA and NSDA neurons following neurotoxicant exposure. The regulation of potential transcription factors for parkin and other neuroprotective pathway genes are of interest since they may provide novel targets for PD disease modifying therapies. As such, we sought to determine if there are time-dependent differences in the expression of AP-1 transcription factors c-Fos, c-Jun, FosB, ΔFosB and JunD in TIDA and NSDA neurons of mice following acute MPTP exposure. We observed that both FosB and ΔFosB expression increase in brain regions containing TIDA, but not NSDA neurons. Furthermore, the nuclear and long-term expression of ΔFosB is consistent with its role as a transcription factor that may influence parkin transcription, which may underlie the unique ability of TIDA neurons to recovery from an injury that leads NSDA neurons to degeneration.