A Modified Arrestin1 Increases Lactate Production in the Retina and Slows Retinal Degeneration.
A Modified Arrestin1 Increases Lactate Production in the Retina and Slows Retinal Degeneration.
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一种修饰的抑制蛋白1增加视网膜中乳酸的产生并减缓视网膜变性。
DOI：
10.1089/hum.2021.272
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发表时间：
2022-07
影响因子：
4.2
通讯作者：
Smith, W. Clay
中科院分区：
文献类型：
--
作者：
Nelson, Tiffany S.;Simpson, Chiab;Dyka, Frank;Dinculescu, Astra;Smith, W. Clay
视网膜中的葡萄糖代谢是精心安排的，葡萄糖通过视网膜色素上皮（RPE）从脉络膜循环传递到光感受器。在光感受器中，葡萄糖主要通过有氧糖酵解进行处理，从中产生的乳酸副产物提供给RPE和米勒胶质细胞以满足它们的能量需求。在这项研究中，我们利用一种修饰的arrestin1蛋白，通过解除烯醇化酶1活性的抑制，来提高杆状光感受器的乳酸糖酵解输出，目的是利用这种增加的乳酸生产作为一种基因不可知的方法来减缓视网膜变性。将E362G/D363G氨基酸取代的小鼠arrestin1（简称“ArrGG”）包装到AAV中，并测试其安全性和增加视网膜乳酸生成的有效性。在C57BL/6J小鼠中，ArrGG的过表达并未导致视网膜电图（ERG）功能或通过外核层（ONL）厚度测量的光感受器存活率的任何可检测到的变化。然而，表达ArrGG的小鼠视网膜显示乳酸分泌率增加~ 25%。因此，我们将AAV-ArrGG通过玻璃体内传递给杂合子P23H视紫红质敲除蛋白小鼠（RhoP23H/+），以确定增强光感受器的糖酵解是否可以减缓视网膜色素变性动物模型的视网膜变性。我们发现ArrGG在这些小鼠中的表达减缓了暗位和光位ERG功能的下降。相应的，与对照组相比，ArrGG处理的RhoP23H/+小鼠的ONL厚度有明显的保留。总之，我们的研究表明，在C57BL/6J小鼠视网膜中表达ArrGG导致乳酸生成增加，与糖酵解上调一致。在色素性视网膜炎的P23H视紫质模型中，ArrGG的表达导致光感受器功能的显著保存和视网膜变性的减缓。这些发现表明，通过光感受器中修饰的抑制蛋白1靶向烯醇化酶1活性的增加来增强糖酵解可能提供一种减缓视网膜变性的治疗方法。
Glucose metabolism in the retina is carefully orchestrated, with glucose being delivered to photoreceptors from the choroidal circulation through the retinal pigmented epithelium (RPE). In photoreceptors, glucose is processed principally by aerobic glycolysis, from which the lactate byproduct is provided to the RPE and Müller glia for their energetic needs. In this study, we utilize a modified arrestin1 protein to enhance the glycolytic output of lactate from rod photoreceptors through disinhibition of enolase1 activity with the goal being to use this increased lactate production as a gene-agnostic approach to slowing retinal degeneration. Mouse arrestin1 with E362G/D363G amino acid substitutions (referred to as “ArrGG”) was packaged into AAV and tested for safety and for efficacy in increasing retinal lactate production. Overexpression of ArrGG in C57BL/6J mice did not result in any detectable changes in either electroretinogram (ERG) function or photoreceptor survival as measured by outer nuclear layer (ONL) thickness. However, mouse retinas expressing ArrGG showed a ∼25% increase in the rate of lactate secretion. Therefore, AAV-ArrGG was delivered intravitreally to heterozygous P23H rhodopsin knockin mice (RhoP23H/+) to determine if enhancing glycolysis in photoreceptors can slow retinal degeneration in this animal model of retinitis pigmentosa. We found that the expression of ArrGG in these mice slowed the decline of both scotopic and photopic ERG function. Correspondingly, there was significant preservation of ONL thickness in RhoP23H/+ mice treated with ArrGG compared with controls. In conclusion, our studies show that expressing ArrGG in C57BL/6J mouse retina results in an increase in lactate production, consistent with an upregulation of glycolysis. In the P23H rhodopsin model of retinitis pigmentosa, the expression of ArrGG led to significant preservation of photoreceptor function and slowing of retinal degeneration. These findings suggest that enhancing glycolysis by targeting increased enolase1 activity with a modified arrestin1 in photoreceptors may offer a therapeutic approach to slowing retinal degeneration.
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影响因子：
4.8
作者：
Nair, KS;Hanson, SM;Slepak, VZ
通讯作者：
Slepak, VZ
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
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影响因子：
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作者：
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影响因子：
17.8
作者：
Berger, Wolfgang;Kloeckener-Gruissem, Barbara;Neidhardt, John
通讯作者：
Neidhardt, John
影响因子：
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作者：
Hauswirth, William W.;Aleman, Tomas S.;Jacobson, Samuel G.
通讯作者：
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