Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Cell Death Dis. 2013 Feb 7;4(2):e488. doi: 10.1038/cddis.2013.12.
For most neurodegenerative diseases the precise duration of an individual cell's death is unknown, which is an obstacle when counteractive measures are being considered. To address this, we used the rd1 mouse model for retinal neurodegeneration, characterized by phosphodiesterase-6 (PDE6) dysfunction and photoreceptor death triggered by high cyclic guanosine-mono-phosphate (cGMP) levels. Using cellular data on cGMP accumulation, cell death, and survival, we created mathematical models to simulate the temporal development of the degeneration. We validated model predictions using organotypic retinal explant cultures derived from wild-type animals and exposed to the selective PDE6 inhibitor zaprinast. Together, photoreceptor data and modeling for the first time delineated three major cell death phases in a complex neuronal tissue: (1) initiation, taking up to 36 h, (2) execution, lasting another 40 h, and finally (3) clearance, lasting about 7 h. Surprisingly, photoreceptor neurodegeneration was noticeably slower than necrosis or apoptosis, suggesting a different mechanism of death for these neurons.
对于大多数神经退行性疾病，个体细胞死亡的确切持续时间尚不清楚，这在考虑对抗措施时是一个障碍。为了解决这个问题，我们使用 rd1 小鼠模型进行视网膜神经退行性变的研究，该模型的特征是磷酸二酯酶-6（PDE6）功能障碍和光感受器死亡，由高环鸟苷单磷酸（cGMP）水平触发。利用关于 cGMP 积累、细胞死亡和存活的细胞数据，我们创建了数学模型来模拟退化的时间发展。我们使用源自野生型动物的器官型视网膜外植体培养物并暴露于选择性 PDE6 抑制剂扎普林司特来验证模型预测。综合光感受器数据和建模结果，首次在复杂的神经元组织中描绘了三个主要的细胞死亡阶段：（1）启动阶段，持续长达 36 小时；（2）执行阶段，持续另外 40 小时；最后是（3）清除阶段，持续约 7 小时。令人惊讶的是，光感受器神经退行性变明显慢于坏死或凋亡，这表明这些神经元的死亡机制不同。
