Arango-Gonzalez Blanca, Trifunović Dragana, Sahaboglu Ayse, Kranz Katharina, Michalakis Stylianos, Farinelli Pietro, Koch Susanne, Koch Fred, Cottet Sandra, Janssen-Bienhold Ulrike, Dedek Karin, Biel Martin, Zrenner Eberhart, Euler Thomas, Ekström Per, Ueffing Marius, Paquet-Durand François
Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.
Department of Neurobiology, University of Oldenburg, Oldenburg, Germany.
PLoS One. 2014 Nov 13;9(11):e112142. doi: 10.1371/journal.pone.0112142. eCollection 2014.
Cell death in neurodegenerative diseases is often thought to be governed by apoptosis; however, an increasing body of evidence suggests the involvement of alternative cell death mechanisms in neuronal degeneration. We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death. We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance. Hallmark features of this pathway are activation of histone deacetylase, poly-ADP-ribose-polymerase, and calpain, as well as accumulation of cyclic guanosine monophosphate and poly-ADP-ribose. Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.
神经退行性疾病中的细胞死亡通常被认为是由凋亡所调控的；然而，越来越多的证据表明，其他细胞死亡机制也参与了神经元的退化过程。我们使用10种不同的动物模型研究视网膜神经退行性变，这些模型涵盖了人类遗传性失明的所有主要类型（rd1、rd2、rd10、Cngb1基因敲除、Rho基因敲除、S334ter、P23H、Cnga3基因敲除、cpfl1、Rpe65基因敲除），通过研究与不同形式细胞死亡相关的代谢过程。我们发现，凋亡在我们所研究的遗传性视网膜神经退行性变形式中仅起次要作用，相反，所有突变体共有的一种非凋亡性退化机制才是至关重要的。该途径的标志性特征是组蛋白脱乙酰酶、聚ADP核糖聚合酶和钙蛋白酶的激活，以及环磷酸鸟苷和聚ADP核糖的积累。因此，我们的研究证明了替代细胞死亡机制在遗传性视网膜变性中的普遍性，并为设计不依赖于突变的治疗方法提供了合理依据。
