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浙江大学学报(医学版)  2022, Vol. 51 Issue (3): 380-387    DOI: 10.3724/zdxbyxb-2022-0024
综述     
囊泡转运在肌萎缩侧索硬化中的作用研究进展
杨朝森,张晓明
浙江大学基础医学院解剖与组织胚胎学系,浙江 杭州 310058
Research progress on vesicular trafficking in amyotrophic lateral sclerosis
YANG Chaosen,ZHANG Xiaoming
Department of Human Anatomy and Embryology, School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China
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摘要:

囊泡转运是细胞利用囊泡完成细胞与环境间或细胞内各细胞器之间物质运输的基本生理过程。近年来,越来越多证据表明囊泡转运障碍在神经退行性疾病发病中起到关键作用。错误折叠蛋白质在异常囊泡转运的介导下,通过内吞作用、内体-溶酶体途径运输、内体逃逸和外泌体释放等方式,实现其在细胞间的传播,进一步加速疾病进展。肌萎缩侧索硬化(ALS)是一种以上下运动神经元的选择性死亡为特征的神经退行性疾病,其多种致病基因均与囊泡转运密切相关,如C9ORF72TARDBPSOD1等,能导致囊泡转运功能障碍。因此,通过调控囊泡转运相关蛋白,能阻止错误折叠蛋白质的沉积和传播,从而起到延缓ALS疾病发展的作用。本文通过综述文献,阐述了囊泡转运在ALS中的重要分子机制,以期为理解ALS致病机制和寻找潜在治疗手段提供新的视角。

关键词: 神经退行性疾病肌萎缩侧索硬化囊泡转运外泌体综述    
Abstract:

Vesicular trafficking is a basic physiological process by which vesicles transport materials between cells and environment (intercellular transport) and between different cellular compartments (intracellular trafficking). In recent years, more and more evidences have suggested that vesicular trafficking dysfunction plays a key role in pathogenesis of neurodegenerative diseases. Abnormal vesicular trafficking promotes the propagation of misfolded proteins by mechanisms involving endocytosis, endosomal-lysosomal pathway, endosomal escape and exosome release, leading to further acceleration of disease progression. Amyotrophic lateral sclerosis (ALS), as a neurodegenerative disease, is characterized by the selective death of upper and lower motor neurons. A variety of causative genes for ALS have been implicated in vesicle trafficking dysfunction, such as C9ORF72, TARDBP and SOD1. Therefore, the aggregation and propagation of misfolded proteins may be prevented through regulation of vesicle trafficking-related proteins, thus delay the progression of ALS. A more in-depth understanding of vesicular trafficking in ALS will be helpful in revealing the mechanism and clinical treatment of ALS. This review focuses on molecular mechanisms of vesicular trafficking in ALS, to provide reference for exploring new therapeutic strategies.

Key words: Neurodegenerative disease    Amyotrophic lateral sclerosis    Vesicular trafficking    Exosome    Review
收稿日期: 2022-01-30 出版日期: 2022-09-21
CLC:  R741  
通讯作者: 张晓明   
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引用本文:

杨朝森,张晓明. 囊泡转运在肌萎缩侧索硬化中的作用研究进展[J]. 浙江大学学报(医学版), 2022, 51(3): 380-387.

YANG Chaosen,ZHANG Xiaoming. Research progress on vesicular trafficking in amyotrophic lateral sclerosis. J Zhejiang Univ (Med Sci), 2022, 51(3): 380-387.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0024        https://www.zjujournals.com/med/CN/Y2022/V51/I3/380

图 1  错误折叠蛋白质通过囊泡转运途径的传播模式

发现年份

基因

蛋白

在囊泡转运中的作用

1992

SOD1

超氧化物歧化酶1

通过大型胞饮作用入胞[44],通过外泌体方式分泌[47],促进类朊样病毒传播

2001

ALS2

Alsin蛋白

通过改变RAB活性形式调节内体的运输和成熟[48]

2004

VAPB

囊泡相关膜蛋白相关蛋白B

通过与RAB7相互作用影响晚期内体形成和外泌体生物发生[49]

2006

CHMP2B

带电荷的多囊泡体蛋白2B

调节多泡体的生物发生[50]

2008

TARDBP

TARDNA结合蛋白43

通过内吞作用对细胞产生毒性[41],参与循环内体运输[42]

2009

FUS

肉瘤融合蛋白

形成聚集体影响内体-溶酶体途径[51]

2009

FIG4

FIG4蛋白

阻断内体-溶酶体途径,可能影响细胞外囊泡分泌[52]

2010

OPTN

视神经蛋白

通过与RAB8相互作用参与囊泡转运[53]

2010

VCP

缬络胺酸蛋白

参与网格蛋白依赖的内吞作用[54]

2010

ATXN2

共济失调蛋白2

参与突触小泡的内吞作用[55]

2010

SPG11

Spatacsin蛋白

阻断内体-溶酶体途径,可能影响细胞外囊泡分泌[56]

2010

TMEM106B

跨膜蛋白106B

影响内体-溶酶体途径[57]

2011

C9ORF72

C9ORF72蛋白

作为GEF通过调节RAB蛋白活性,参与内体运输和外泌体分泌过程[24]

2011

SQSTM1

P62蛋白

影响内体-溶酶体途径后续的自噬降解过程[58]

2011

UBQLN2

泛素样蛋白2

通过RAB11阳性循环内体参与自噬[59]

2015

TBK-1

TBK-1蛋白

影响内体-溶酶体途径后续的自噬降解过程[60]

2017

ANXA11

膜联蛋白11

借助晚期内体或溶酶体协助RNA运输[61]

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