The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro.
The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro.
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E50K optineurin 突变影响自噬介导的 TDP-43 降解，并导致体内和体外 RGC 凋亡
DOI：
10.1038/s41420-021-00432-0
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发表时间：
2021-03-15
影响因子：
7
通讯作者：
Yuan H
中科院分区：
文献类型：
--
作者：
Zhang S;Shao Z;Liu X;Hou M;Cheng F;Lei D;Yuan H
视神经磷酸酶（optineurin，OPTN）E50 K突变是视网膜神经节细胞（retinalganglioncells，RGCs）自噬和凋亡的重要机制之一。在这项研究中，我们研究了OPTN（E50 K）突变是否通过破坏体内和体外自噬引起TDP-43聚集。产生OPTN（E50 K）突变小鼠并分析基因型和表型。使用含有仅GFP、GFP标记的野生型OPTN或GFP标记的E50 K突变的OPTN的腺相关病毒2型载体来转染R28细胞。与WT小鼠相比，在OPTN（E50 K）小鼠中观察到RGC的丧失降低了视网膜厚度和视觉损害。E50 K OPTN过表达可诱导R28细胞凋亡。增加的p62/SQSTM 1和LC 3-II水平表明自噬通量被抑制，并有助于TDP-43在体内和体外的聚集。我们发现，雷帕霉素有效地减少了TDP-43在OPTN（E50 K）小鼠中的聚集，并降低了p62/SQSTM 1和自噬标志物LC 3-II的蛋白水平。此外，雷帕霉素增加了E50 K小鼠的RGC数量和视觉功能。此外，我们还观察到24月龄OPTN（E50 K）小鼠脊髓中胞浆TDP-43增加和运动功能障碍，表明TDP-43蓄积可能是青光眼和肌萎缩侧索硬化（ALS）的共同病理机制。总之，OPTN（E50 K）对自噬的破坏影响了TDP-43的降解，并可能在OPTN（E50 K）介导的青光眼性视网膜神经变性中发挥重要作用。
The glaucoma-associated E50K mutation in optineurin (OPTN) is known to affect autophagy and cause the apoptosis of retinal ganglion cells (RGCs), but the pathogenic mechanism remains unclear. In this study, we investigated whether the OPTN (E50K) mutation caused TDP-43 aggregation by disrupting autophagy in vivo and in vitro. OPTN (E50K) mutant mice were generated and analysed for genotype and phenotype. Adeno-associated virus type 2 vectors containing either GFP only, GFP-tagged wild-type OPTN or GFP-tagged E50K-mutated OPTN were used to transfect R28 cells. Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice. Moreover, overexpression of E50K OPTN induced R28 cell apoptosis. Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro. We found that rapamycin effectively reduced the aggregation of TDP-43 in OPTN (E50K) mice and decreased the protein levels of p62/SQSTM1 and the autophagic marker LC3-II. Moreover, rapamycin increased the RGC number and visual function of E50K mice. In addition, we also observed increased cytoplasmic TDP-43 in the spinal cord and motor dysfunction in 24-month-old OPTN (E50K) mice, indicating that TDP-43 accumulation may be the common pathological mechanism of glaucoma and amyotrophic lateral sclerosis (ALS). In conclusion, the disruption of autophagy by OPTN (E50K) affected the degradation of TDP-43 and may play an important role in OPTN (E50K)-mediated glaucomatous retinal neurodegeneration.
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