Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model.
Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model.
复制标题
自噬对DBA/2J自发性青光眼小鼠模型中的眼高血压和神经退行性的贡献。
DOI：
10.1038/s41420-018-0077-y
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发表时间：
2018
影响因子：
7
通讯作者：
Liton PB
中科院分区：
文献类型：
--
作者：
Hirt J;Porter K;Dixon A;McKinnon S;Liton PB
青光眼是一种以轴突变性和视网膜神经节细胞丧失为特征的进行性视神经病变。有几个因素被认为在青光眼中起作用，眼压升高（IOP）是最著名的病因。导致高眼压和青光眼的机制尚不完全清楚。越来越多的证据表明，自噬在高眼压和青光眼的病理生理过程中起着重要作用。然而，尽管所有的研究都认为自噬在RGCs中被诱导以应对损伤，但根据所使用的实验模型，自噬被发现可以保护或促进细胞死亡。为了进一步了解自噬在青光眼发病机制中的作用以及慢性IOP升高在自噬通路中的作用，我们首次在本实验室产生的自发性高眼压DBA/2J小鼠青光眼模型和转基因DBA/2J::GFP-LC3小鼠中，研究了虹膜角膜角区、视网膜神经节细胞体和ON轴突的自噬。我们的研究结果表明，通过western blot和免疫荧光检测，DBA/2J小鼠流出通道细胞的自噬通量降低，其特征是LC3-II和p62水平升高，同时溶酶体标志物LAMP1降低。在DBA/2J，尤其是DBA/2J::GFP-LC3小鼠中也观察到自噬空泡的升高。在DBA/2J背景下，GFP-LC3转基因基因的表达与较高的累积IOP相关。与DBA/2J相比，除了IOP升高外，DBA/2J::GFP-LC3的特征是进一步的RGCs和加重的轴突变性。这伴随着退化轴突内显著的高自噬数字的存在。这些结果强烈提示过度激活自噬是导致慢性高血压DBA/2J小鼠ON变性的潜在细胞机制。
Glaucoma is a progressive optic neuropathy characterized by axonal degeneration and retinal ganglion cells loss. Several factors have been postulated to play a role in glaucoma, elevated intraocular pressure (IOP) being the best well-known causative factor. The mechanisms leading to ocular hypertension and glaucoma are still not fully understood. An increasing number of evidence indicates a role of autophagy in the pathophysiological process of ocular hypertension and glaucoma. However, while all of the studies agree that autophagy is induced in RGCs in response to injury, autophagy was found to either protect or promote cell death depending on the experimental model used. In order to gain more insight into both, the role of autophagy in the pathogenesis of glaucoma and the effect of chronic IOP elevation in the autophagy pathway, we have investigated here for the first time autophagy in the iridocorneal angle region, retinal ganglion cell bodies, and ON axons in the spontaneous ocular hypertensive DBA/2J mouse glaucoma model and in the transgenic DBA/2J::GFP-LC3 mice, generated in our laboratory. Our results indicate decreased autophagic flux in the outflow pathway cells in the DBA/2J mice, characterized by increased levels of LC3-II and p62 together with a decrease in the lysosomal marker LAMP1, evaluated by western blot and immunofluorescence. Elevated presence of autophagic vacuoles in the DBA/2J and, in particular, in the DBA/2J::GFP-LC3 mice was also observed. Expression of the GFP-LC3 transgene was associated to higher cumulative IOP in the DBA/2J background. In addition to higher elevation in IOP, DBA/2J::GFP-LC3 were characterized by further RGCs and exacerbated axonal degeneration compared to DBA/2J. This was accompanied by the notable high presence of autophagic figures within degenerating axons. These results strongly suggest overactivation of autophagy as a potential cellular mechanism leading to ON degeneration in the chronic hypertensive DBA/2J mice.
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影响因子：
9
作者：
通讯作者：
--
DOI：
10.1016/j.bbadis.2014.11.021
发表时间：
2015-03
影响因子：
6.2
作者：
Porter, Kristine;Hirt, Joshua;Stamer, W. Daniel;Liton, Paloma B.
通讯作者：
Liton, Paloma B.
影响因子：
9
作者：
通讯作者：
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DOI：
10.3129/canjophthalmol.i07-036
发表时间：
2007-04-01
影响因子：
4.2
作者：
Nickells, Robert W.
通讯作者：
Nickells, Robert W.
影响因子：
15.9
作者：
Marino, Guillermo;Fernandez, Alvaro F.;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos