Department of Neurobiology and Genetics, Institute of Genetics and Molecular and Cellular Biology (IGBMC), UMR 7104-CNRS/INSERM/UdS, BP10142, 67404 Illkirch Cédex, France.
Neurobiol Dis. 2010 Oct;40(1):311-24. doi: 10.1016/j.nbd.2010.06.005. Epub 2010 Jun 18.
In neurodegenerative disorders caused by polyglutamine (polyQ) expansion, polyQ toxicity is thought to trigger a linear cascade of successive degenerative events leading to neuronal death. To understand how neurons cope with polyQ toxicity, we studied a Spinocerebellar ataxia 7 (SCA7) mouse which expresses polyQ-expanded ATXN7 only in rod photoreceptors. We show that in response to polyQ toxicity, SCA7 rods go through a range of radically different cell fates, including apoptotic and non-apoptotic cell death, cell migration, morphological transformation into a round cell or, most remarkably, cell division. The temporal profile of retinal remodeling indicates that some degenerative pathways are triggered early in the disease but decline later on, while others worsen progressively. Retinal remodeling results in a relative maintenance of photoreceptor population, but does not preserve the retinal function. Rod responses to proteotoxicity correlate with the nature, level and ratio of mutant ATXN7 species. The multifaceted response of neurons to polyQ toxicity is an important concept for the design of therapeutic strategies.
在由多聚谷氨酰胺（polyQ）扩展引起的神经退行性疾病中，polyQ 毒性被认为引发了一系列连续的退行性事件，导致神经元死亡。为了了解神经元如何应对 polyQ 毒性，我们研究了一种仅在杆状光感受器中表达 polyQ 扩展的 ATXN7 的脊髓小脑共济失调 7（SCA7）小鼠。我们表明，对 polyQ 毒性的反应中，SCA7 杆状细胞经历了一系列截然不同的细胞命运，包括凋亡和非凋亡性细胞死亡、细胞迁移、形态转化为圆形细胞，或者最显著的是细胞分裂。视网膜重塑的时间进程表明，一些退行性途径在疾病早期被触发，但后来会下降，而另一些则逐渐恶化。视网膜重塑导致光感受器群体的相对维持，但不能保留视网膜功能。杆状细胞对蛋白毒性的反应与突变 ATXN7 物种的性质、水平和比例有关。神经元对 polyQ 毒性的多方面反应是设计治疗策略的一个重要概念。
