AAV2-mediated GRP78 Transfer Alleviates Retinal Neuronal Injury by Downregulating ER Stress and Tau Oligomer Formation.
AAV2-mediated GRP78 Transfer Alleviates Retinal Neuronal Injury by Downregulating ER Stress and Tau Oligomer Formation.
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DOI：
10.1167/iovs.18-24427
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发表时间：
2018-09-04
影响因子：
4.4
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Ha Y;Liu W;Liu H;Zhu S;Xia F;Gerson JE;Azhar NA;Tilton RG;Motamedi M;Kayed R;Zhang W
外伤性视神经病变(TON)轴突损伤后视网膜神经节细胞(RGC)死亡可导致不可逆性视力丧失。GRP78是一种分子伴侣，能促进蛋白质折叠并控制内质网(ER)应激途径的激活。本研究确定了腺相关病毒(AAV)介导的GRP78基因转移对视神经挤压(ONC)诱导的视神经损伤(ONC)小鼠视网膜神经节细胞的保护作用。ONC是由眼球后面的视神经一过性挤压引起的。AAV被用来将基因输送到视网膜。免疫组织化学和免疫印迹法检测内质网应激分支、tau寡聚体和RGC损伤的分子。在所测试的AAV血清型中，AAV2是向RGC运送基因的最有效的。AAV2-GRP78玻璃体内注射显著减轻内质网应激和视网膜神经节细胞死亡，并显著改善视网膜神经节细胞存活和功能。蛋白质聚集在内质网应激过程中增加，聚集的蛋白质，如tau寡聚体，是神经退行性疾病的关键角色。AAV2-GRP78可减轻ONC诱导的tau磷酸化和寡聚化的增加。此外，tau寡聚体直接诱导RGC死亡，并用tau寡聚体单抗(TOMA)阻断tau寡聚体可减轻ONC诱导的RGC丢失。这些数据表明，AAV2-GRP78的有益作用部分是通过减少错误折叠的tau来实现的，并提供了令人信服的证据，表明AAV2-GRP78的基因治疗或TOMA免疫治疗为减轻Ton的RGC丢失提供了新的治疗途径。
Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene transfer of GRP78 protected RGCs from death in a mouse model of TON induced by optic nerve crush (ONC). ONC was induced by a transient crush of optic nerve behind the eye globe. AAV was used to deliver genes into retina. Molecules in the ER stress branches, tau oligomers, and RGC injury were determined by immunohistochemistry or Western blot. Among tested AAV serotypes, AAV2 was the most efficient for delivering genes to RGCs. Intravitreal delivery of AAV2-GRP78 markedly attenuated ER stress and RGC death 3 days after ONC, and significantly improved RGC survival and function 7 days after ONC. Protein aggregation is increased during ER stress and aggregated proteins such as tau oligomers are key players in neurodegenerative diseases. AAV2-GRP78 alleviated ONC-induced increases in tau phosphorylation and oligomerization. Furthermore, tau oligomers directly induced RGC death, and blocking tau oligomers with tau oligomer monoclonal antibody (TOMA) attenuated ONC-induced RGC loss. These data indicate that the beneficial effect of AAV2-GRP78 is partially mediated by the reduction of misfolded tau, and provide compelling evidence that gene therapy with AAV2-GRP78 or immunotherapy with TOMA offers novel therapeutic approaches to alleviate RGC loss in TON.
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影响因子：
5.3
作者：
Castillo-Carranza, Diana L.;Sengupta, Urmi;Kayed, Rakez
通讯作者：
Kayed, Rakez
影响因子：
4
作者：
Castillo-Carranza, Diana L.;Gerson, Julia E.;Kayed, Rakez
通讯作者：
Kayed, Rakez
影响因子：
4.4
作者：
Gabriele, Michelle L.;Ishikawa, Hiroshi;Wollstein, Gadi
通讯作者：
Wollstein, Gadi
影响因子：
2.1
作者：
Bell MC;Meier SE;Ingram AL;Abisambra JF
通讯作者：
Abisambra JF
DOI：
10.1080/10409238.2016.1226251
发表时间：
2016
影响因子：
6.5
作者：
Gerson JE;Mudher A;Kayed R
通讯作者：
Kayed R