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Roles of optineurin and Extracellular Vesicles in Glaucomatous Retinal Cell Loss

Current Medical Science 2023年第2期43卷 367-375页

作者： Chao-ye DUAN Wan-lin FAN Fei CHEN Department of Ophthalmology Renmin Hospital of Wuhan UniversityWuhan430060China Department of Ophthalmology University of CologneFaculty of Medicine and University Hospital CologneCologne50937Germany Department of Ophthalmology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China

Objective To explore the role of extracellular vesicles(EVs)in the pathogenesis of glaucoma caused by E50K *** A photoreceptor cell line,RGC-5,was transfected with empty plasmids and plasmids expressing wild-type(WT)optineurin(OPTN)or E50K OPTN to investigate the effects of OPTN glaucoma as well as to identify the role of EVs in glaucoma *** RGC-5 cells were also stimulated with glutamate,and their viability was evaluated using flow cytometry or CCK-8 *** were extracted,labeled with PKH-26,and added into the medium for normal RGC-5 culture,and the status of the cells was observed *** WT OPTN overexpression,E50K OPTN,and glutamate stimulation induced apoptosis of RGC-5 ***,when glutamate stimulation was used as an add-on treatment,the degree of apoptosis in WT OPTN-overexpressing RGC-5 cells was significantly lower than that in E50K OPTN-expressing and normal RGC-5 *** viability of normal RGC-5 cells was reduced when co-cultured with WT OPTN-overexpressing RGC-5 or E50K OPTN-overexpressing *** released by the latter two transfected lines similarly reduced normal RGC-5 *** Our results indicate that WT OPTN overexpression may lead to photoreceptor ***,overexpression also confers a degree of protection against high concentrations of extracellular ***,EVs released by transfected RGC-5 cells may regulate the cell *** findings may improve our understanding of the mechanisms of cell-cell interactions in pathological conditions,providing a basis for the use of EVs as novel targets for early diagnosis and treatment of glaucoma.

关键词： E50K mutation extracellular vesicles glaucoma optineurin RGC-5 photoreceptor cell line

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optineurin SEQUENCE VARIANTS IN BRITISH GLAUCOMA SUBJECTS

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国际眼科杂志 2003年第1期3卷 97-98页

作者： T.Aung N.Ebenezer G.Brice A.Child R.Hitchings O.Lehmann S.Bhattacharya Institute of Ophthalmology University Col-lege Singapore National Eye CentreInstitute of Ophthalmology University Col-legeSt George&#8217 S Hospital Med School UKSt George&#8217 S Hospital Med School UKMoorfields Eye HospitalInstitute of Ophthalmology University Col-lege Moorfields Eye HospitalInstitute of Ophthalmology University Col-lege

Aim: A recent study found that the optineurin (OPTN) gene was mutated in families with primary open angle glaucoma (POAG), A misense mutation E50K was present in 13.5% of families studied, and the M98K risk-associated... 详细信息

关键词：青光眼英国患者 optineurin 基因突变 POAG

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Identification of the Stress Which Causes optineurin Aggregation

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Neuroscience & Medicine 2019年第2期10卷 150-161页

作者： Satoshi Inagaki Michinori Funato Junko Seki Chizuru Kawase Kazuki Ohuchi Shiori Ando Shinsuke Nakamura Masamitsu Shimazawa Hideo Kaneko Hideaki Hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Department of Clinical Research National Hospital Organization Nagara Medical Center Gifu Japan

Glaucoma is a common neurodegenerative disease that can cause blindness and occurs worldwide. Currently, lowering intraocular pressure is the only therapy available to protect retinal ganglion cells (RGCs). However, this therapy does not prevent RGC death in all patients. Therefore, new therapeutic approaches for glaucoma are urgently required, and neuroprotection of RGCs is a focus for many researchers. optineurin (OPTN) is one of the normal tension glaucoma (NTG) relative genes, while mutant OPTN can form a characteristic aggregation, causing RGC death. Hence, elucidation of the mechanism of OPTN aggregation might provide a clue to help understand RGC death. To examine whether non-mutant OPTN could also aggregate, we pharmacologically induced some glaucoma-related stresses, such as endoplasmic reticulum (ER) stress, glutamate toxicity, activation of TNF-α signaling, mitochondrial dysfunction, and autophagic flux impairment. Our results showed that ER stress, TNF-α signaling, and autophagic flux are involved in OPTN aggregation. Furthermore, our data indicated that increased ER stress, activation of TNF-α signaling, and impaired autophagic flux induce OPTN aggregation, suggesting that OPTN aggregation might be an important therapeutic target not only for familial NTG with mutated OPTN but also for patients with glaucoma more generally.

关键词： Glaucoma Induced Pluripotent Stem Cells Retinal Ganglion Cells optineurin Protein Aggregation

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成人发病的原发性开角型青光眼患者中optineurin突变与疾病间缺少相关性

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美国医学会眼科杂志（中文版） 2004年第2期16卷 125-125页

作者： JaneyL.Wiggs JosetteAuguste R.RandAllingham JasonD.Flor MargaretA.Pericak-Vance kathrynRogers KarenR.LaRocque FeliciaL.Graham BobBroomer ElizabethDelBono JonathanL.Haires MichaelHauser 齐越

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Mitochondrial quality control in amyotrophic lateral sclerosis：towards a common pathway？

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Neural Regeneration Research 2017年第7期12卷 1052-1061页

作者： Bilal Khalil Jean-Charles Liévens Department of Neuroscience Mayo Clinic Florida Jacksonville FL USA MMDN Université de Montpellier EPHE INSERM U1198 Montpellier France

Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor *** mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS ***,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS *** such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through *** evidence shows that ALS-related genes interfere with the mitochondrial quality control *** review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.

关键词： C9orf72 FUS SOD1 optineurin Parkin PGC-1α PINK1 TDP-43 proteinopathies TBK1 VCP

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Neutralizing peripheral circulating IL1β slows the progression of ALS in a lentivirus-infected OPTN^(E478G)mouse model

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Animal Models and Experimental Medicine 2023年第1期6卷 18-25页

作者： Wen-Bao Hu Xin Wang Zhi-Lin Pang Ran Duan Chun-Gu Hong Zheng-Zhao Liu Xiangya Hospital Central South UniversityChangshaChina

Background:Amyotrophic lateral sclerosis(ALS)is irreversible and fatal within 3-5 years,with limited options for *** is imperative to develop a symptom-based treatment that may increase the survival of ALS patients and improve their quality of *** status,especially elevated interleukin 1β(IL1β),has been reported to play a critical role in ALS *** study determined that neutralizing circulating IL1βslows down the progression of ALS in an ALS mouse ***:The ALS mouse model was developed by microinjection of lentivirus-carrying OPTN^(E478G)(optineurin,a mutation from ALS patients)into the intra-motor cortex of *** circulating IL1βwas neutralized by injecting anti-IL1βan-tibody into the tail ***-linked immunosorbent assay(ELISA)and real-time polymerase chain reaction(RT-PCR)were carried out to determine the protein and gene expression levels of IL1β.TUNEL assay was used to assess the neural cell *** staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell *** fibrillary acidic protein staining was performed to ana-lyze the number of *** test,grip strength test,balance beam test,and footprint test were conducted to assess the locomotive function after anti-IL1β***:The model revealed that neuroinflammation contributes to ALS *** mice exhibited elevated neuroinflammation and IL1β*** anti-IL1βtreatment,ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ***:Blocking IL1βis a promising strategy to slow down the progression of ALS.

关键词： amyotrophic lateral sclerosis inflammation interleukin 1β neurodegeneration optineurin

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Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

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Phenomics 2023年第2期3卷 167-181页

作者： Siqi Dong Xianhong Yin Kun Wang Wenbo Yang Jiatong Li Yi Wang Yanni Zhou Xiaoni Liu Jiucun Wang Xiangjun Chen Department of Neurology Huashan Hospital and Institute of NeurologyFudan UniversityShanghai 200040China National Center for Neurological Disorders Shanghai 200040China Department of Anthropology and Human Genetics School of Life SciencesFudan UniversityShanghai 200438China Human Phenome Institute Fudan UniversityShanghai 200433China

Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disorder with phenotypic and genetic *** studies have suggested an oligogenic basis of ALS,in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious *** assess the contribution of possible oligogenic inheritance,we profiled a panel of 43 relevant genes in 57 sporadic ALS(sALS)patients and eight familial ALS(fALS)patients from five pedigrees in east *** filtered rare variants using the combination of the Exome Aggregation Consortium,the 1000 Genomes and the HuaBiao *** analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype–phenotype ***,we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes,among which two sALS and four fALS patients harbored two or more *** note,the sALS patients with one or more variants in ALS genes had worse survival than the patients with no ***,in one fALS pedigree with three variants,the family member with three variants(Superoxide dismutase 1(SOD1)p.V48A,optineurin(OPTN)p.A433V and TANK binding kinase 1(TBK1)p.R573H)exhibited much more severe disease phenotype than the member carrying one variant(TBK1 p.R573H).Our findings suggest that rare variants could exert a negative prognostic effect,thereby supporting the oligogenic inheritance of ALS.

关键词： Amyotrophic lateral sclerosis Oligogenic inheritance Survival Superoxide dismutase 1 TANK-binding kinase 1 optineurin

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青光眼致病基因OPTN在大鼠光感受器细胞内的表达

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解剖科学进展 2013年第3期19卷 268-271页

作者：王春霞杨德琪赵宇于紫燕阎启昌张劲松中国医科大学附属第四医院眼科中国医科大学眼科医院辽宁省晶状体重点实验室

目的观察OPTN在大鼠视网膜光感受器细胞内的表达及定位,探讨OPTN和NRL(neural retina leucine zipper)两蛋白相互的作用。方法制备正常Wistar大鼠的视网膜冷冻切片,用抗OPTN抗体、抗NRL抗体和抗CRX抗体分别进行多重免疫荧光染色。结果... 详细信息

目的观察OPTN在大鼠视网膜光感受器细胞内的表达及定位,探讨OPTN和NRL(neural retina leucine zipper)两蛋白相互的作用。方法制备正常Wistar大鼠的视网膜冷冻切片,用抗OPTN抗体、抗NRL抗体和抗CRX抗体分别进行多重免疫荧光染色。结果在外丛状层(OPL)、外核层(ONL)、光感受器细胞内节(IS)、神经节细胞层、内丛状层(IPL)和内核层(INL)中均观察到抗OPTN抗体不同强度的荧光信号。光感受器细胞内的荧光信号主要在细胞质内,而细胞核内未见染色,且具有视锥细胞特征的细胞未被抗OPTN抗体染色。结论 Optn(OPTN的大鼠同源基因)在除视锥细胞以外的光感受器细胞高表达。

关键词： optineurin 免疫荧光染色光感受器大鼠

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