Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland.
Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
Autophagy. 2023 Feb;19(2):388-400. doi: 10.1080/15548627.2022.2069437. Epub 2022 May 1.
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with limited understanding of its pathogenesis and a lack of effective treatment. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to geographic atrophy and/or choroidal neovascularization and fibrosis. The role of macroautophagy/autophagy in AMD pathology is steadily emerging. This review describes selective and secretory autophagy and their role in drusen biogenesis, senescence-associated secretory phenotype, inflammation and epithelial-mesenchymal transition in the pathogenesis of AMD. Aβ: amyloid-beta; AMBRA1: autophagy and beclin 1 regulator 1; AMD: age-related macular degeneration; ATF6: activating transcription factor 6; ATG: autophagy related; BACE1: beta-secretase 1; BHLHE40: basic helix-loop-helix family member e40; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; C: complement; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CFB: complement factor B; DELEC1/Dec1; deleted in esophageal cancer 1; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EMT: epithelial-mesenchymal transition; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; HMGB1: high mobility group box 1; IL: interleukin; KEAP1: kelch like ECH associated protein 1; LAP: LC3-associated phagocytosis; LAMP2: lysosomal associated membrane protein 2; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NFE2L2: NFE2 like bZIP transcription factor 2; NLRP3; NLR family pyrin domain containing 3; NFKB/NFκB: nuclear factor kappa B; OPTN: optineurin; PARL: presenilin associated rhomboid like; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PINK1: PTEN induced kinase 1; POS: photoreceptor outer segment; PPARGC1A: PPARG coactivator 1 alpha; PRKN: parkin RBR E3 ubiquitin protein ligase; PYCARD/ASC: PYD and CARD domain containing; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SA: secretory autophagy; SASP: senescence-associated secretory phenotype; SEC22B: SEC22 homolog B, vesicle trafficking protein; SNAP: synaptosome associated protein; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX: syntaxin; TGFB2: transforming growth factor beta 2; TRIM16: tripartite motif containing 16; TWIST: twist family bHLH transcription factor; Ub: ubiquitin; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; V-ATPase: vacuolar-type H-translocating ATPase; VIM: vimentin.
年龄相关性黄斑变性（AMD）是导致老年人群视力下降的主要原因，但其发病机制尚不完全清楚，且缺乏有效的治疗方法。AMD 的进展最初表现为视网膜色素上皮的萎缩性改变，以及溶酶体脂褐素和细胞外 drusen 沉积物的形成。慢性氧化应激、蛋白质聚集和炎症过程引起的损伤可能导致地图样萎缩和/或脉络膜新生血管和纤维化。巨自噬/自噬在 AMD 病理学中的作用正在逐渐显现。本文描述了选择性自噬和分泌性自噬及其在 drusen 发生、衰老相关分泌表型、炎症和上皮-间充质转化中的作用，这些都是 AMD 发病机制的关键因素。Aβ：淀粉样β；AMBRA1：自噬和 beclin 1 调节因子 1；AMD：年龄相关性黄斑变性；ATF6：激活转录因子 6；ATG：自噬相关；BACE1：β-分泌酶 1；BHLHE40：碱性螺旋-环-螺旋家族成员 e40；BNIP3：BCL2 相互作用蛋白 3；BNIP3L/NIX：BCL2 相互作用蛋白 3 样；C：补体；CALCOCO2/NDP52：钙结合和卷曲螺旋域 2；CARD：半胱氨酸天冬氨酸蛋白酶募集域；CDKN2A/p16：细胞周期蛋白依赖性激酶抑制剂 2A；CFB：补体因子 B；DELEC1/Dec1：食管癌缺失 1；EIF2AK3/PERK：真核翻译起始因子 2α激酶 3；EMT：上皮-间充质转化；ER：内质网；ERN1/IRE1：内质网向核信号 1；FUNDC1：FUN14 结构域包含 1；GABARAP：GABA 型 A 受体相关蛋白；HMGB1：高迁移率族蛋白 B1；IL：白细胞介素；KEAP1：kelch 样 ECH 相关蛋白 1；LAP：LC3 相关吞噬作用；LAMP2：溶酶体相关膜蛋白 2；LIR：LC3 相互作用区域；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；MTOR：雷帕霉素靶蛋白激酶；NFE2L2：NFE2 样 bZIP 转录因子 2；NLRP3：NLR 家族 pyrin 结构域包含 3；NFKB/NFκB：核因子 kappa B；OPTN：optineurin；PARL：早老素相关的 rhomboid 样；PGAM5：PGAM 家族成员 5，线粒体丝氨酸/苏氨酸蛋白磷酸酶；PINK1：PTEN 诱导的激酶 1；POS：光感受器外节；PPARGC1A：PPARG 共激活因子 1 alpha；PRKN：parkin RBR E3 泛素蛋白连接酶；PYCARD/ASC：PYD 和 CARD 结构域包含；ROS：活性氧；RPE：视网膜色素上皮；SA：分泌性自噬；SASP：衰老相关分泌表型；SEC22B：SEC22 同源 B，囊泡转运蛋白；SNAP：突触相关蛋白；SNARE：可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体；SQSTM1/p62：自噬体 1；STX： syntaxin；TGFB2：转化生长因子β 2；TRIM16：三肽重复包含 16；TWIST： twist 家族 bHLH 转录因子；Ub：泛素；ULK：unc-51 样自噬激活激酶；UPR：未折叠蛋白反应；UPS：泛素-蛋白酶体系统；V-ATPase：液泡型 H-转运 ATP 酶；VIM：波形蛋白。
