Komnig Daniel, Schulz Jörg B, Reich Arno, Falkenburger Björn H
Department of Neurology, RWTH University Aachen, Aachen, Germany.
JARA-Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany.
J Neurochem. 2016 Dec;139(5):848-857. doi: 10.1111/jnc.13847. Epub 2016 Oct 11.
The death receptor Fas/CD95 mediates apoptotic cell death in response to external stimuli. In neurons, Fas-induced apoptosis is prevented by Fas-apoptotic inhibitory molecule 2 (Faim2). Mice lacking Faim2 showed increased neurodegeneration in animal models of stroke and bacterial meningitis. We therefore tested the relevance of Faim2 in a classical animal model of Parkinson disease and determined the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Faim2-deficient mice. Without MPTP treatment, there was no difference in the dopaminergic system between Faim2-deficient mice and control mice. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. Fourteen days after the last MPTP injection, the number of dopaminergic neurons in the lateral substantia nigra, assayed by stereological counting, was reduced by 39% in control mice and 53% in Faim2-deficient mice. The density of dopaminergic fibers in the dorsal striatum was reduced by 36% in control mice and 69% in Faim2-deficient mice, in the ventral striatum 44% in control mice and 76% in Faim2-deficient mice. Fiber density recovered at 90 days after MPTP with similar density in both groups. Striatal catecholamine levels were reduced by 81-84% in both groups and recovered at 90 days. Faim2 expression was documented in mouse midbrain using quantitative reverse transcription-PCR (qRT-PCR) and found decreased after MPTP administration. Taken together, our findings demonstrate increased degeneration of dopaminergic neurons with Faim2 deficiency, indicating that Fas-induced apoptosis contributes to cell death in the MPTP mouse model. Along with the decreased expression of Faim2 after MPTP, this finding indicates that boosting Faim2 function might represent a therapeutic strategy for Parkinson disease.
死亡受体Fas/CD95介导细胞对外部刺激作出反应后的凋亡性细胞死亡。在神经元中，Fas凋亡抑制分子2（Faim2）可阻止Fas诱导的凋亡。在中风和细菌性脑膜炎的动物模型中，缺乏Faim2的小鼠神经退行性变增加。因此，我们在帕金森病的经典动物模型中测试了Faim2的相关性，并确定了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）对Faim2缺陷小鼠的毒性。未经MPTP处理时，Faim2缺陷小鼠和对照小鼠的多巴胺能系统无差异。以每千克30毫克的剂量连续5天腹腔注射MPTP。最后一次注射MPTP 14天后，通过体视学计数分析，对照小鼠黑质外侧多巴胺能神经元数量减少了39%，Faim2缺陷小鼠减少了53%。对照小鼠背侧纹状体中多巴胺能纤维密度减少了36%，Faim2缺陷小鼠减少了69%；对照小鼠腹侧纹状体中减少了44%，Faim2缺陷小鼠减少了76%。MPTP处理90天后纤维密度恢复，两组密度相似。两组纹状体儿茶酚胺水平均降低了81 - 84%，并在90天后恢复。使用定量逆转录PCR（qRT-PCR）在小鼠中脑记录到Faim2表达，发现MPTP给药后表达降低。综上所述，我们的研究结果表明，Faim2缺陷会导致多巴胺能神经元退化增加，表明Fas诱导的凋亡在MPTP小鼠模型中导致细胞死亡。连同MPTP后Faim2表达降低，这一发现表明增强Faim2功能可能是帕金森病的一种治疗策略。
