秀丽隐杆线虫作为退行性疾病模型的分子通路研究进展

doi:10.12300/j.issn.1674-5817.2025.134

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (6): 738-751.DOI: 10.12300/j.issn.1674-5817.2025.134

• 无脊椎实验动物：线虫 • 上一篇下一篇

秀丽隐杆线虫作为退行性疾病模型的分子通路研究进展

孙涵¹(), 郭芃², 俞昕何¹, 张隽巧³, 尧莹⁴, 杨文¹()()

^1.上海交通大学医学院基础医学院, 上海 200025
^2.上海交通大学医学院附属仁济医院, 上海 200127
^3.同济大学医学院, 上海 200092
^4.同济大学附属东方医院, 上海 200120

收稿日期:2025-08-12 修回日期:2025-12-05 出版日期:2025-12-25 发布日期:2025-12-19
通讯作者: 杨文（1979—），男，博士，研究员，研究方向：线粒体代谢与衰老。E-mail： yangwen@shsmu.edu.cn。ORCID： 0000-0002-2032-1982
作者简介:孙涵（2000—），女，博士研究生，研究方向：线粒体氧化应激与衰老。E-mail： Ivyyyyy@sjtu.edu.cn。ORCID： 009-0006-2882-6631
基金资助:
国家自然科学基金面上项目“线粒体ROS通过影响邻近区域eIF2α氧化调节微管的新型信号传导机制及其生理意义”(32570834)

Progress in Caenorhabditis elegans as a Degenerative Disease Model for Molecular Pathways Studying

SUN Han¹(), GUO Peng², YU Xinhe¹, ZHANG Junqiao³, YAO Ying⁴, YANG Wen¹()()

^1.Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
^2.Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
^3.Tongji University School of Medicine, Shanghai 200092, China
^4.Shanghai East Hospital, Tongji University, Shanghai 200120, China

Received:2025-08-12 Revised:2025-12-05 Published:2025-12-25 Online:2025-12-19
Contact: YANG Wen (ORCID: 0000-0002-2032-1982), E-mail: yangwen@shsmu.edu.cn

摘要/Abstract

摘要：

随着我国老龄化加速，退行性疾病（degenerative diseases）患者已超过 1 000 万，亟需高效的机制研究与药物筛选体系。秀丽隐杆线虫（Caenorhabditis elegans）因生命周期短、成本低、遗传操作便捷，已成为研究神经退行性疾病的重要模式生物。通过异源表达 β-淀粉样蛋白（amyloid β-protein，Aβ）、α-突触核蛋白（α-synuclein，α-Syn）、突变型超氧化物歧化酶1（superoxide dismutase 1，SOD1）等，或利用 CRISPR/Cas9 基因编辑（clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9，CRISPR/Cas9）构建突变体，可在线虫中重现阿尔茨海默病（Alzheimer's disease，AD）、帕金森病（Parkinson's disease，PD）、肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）和亨廷顿病（Huntington's disease，HD）等典型病理特征。结合 RNA 干扰（RNA interference，RNAi）和化合物筛选，线虫模型已揭示蛋白稳态、自噬和线粒体功能等核心病理通路，并发现多项潜在靶点。未来，依托线虫在遗传学可操作性、表型量化和筛选规模上的独特优势，并结合多模型跨物种验证，将有望构建更具预测性和可转化性的退行性疾病研究与干预体系。

关键词: 秀丽隐杆线虫, 退行性疾病, 模式生物, 神经退行性疾病

Abstract:

With the acceleration of population aging in China, the number of patients with degenerative diseases has exceeded ten million, urgently requiring efficient mechanism research and drug screening systems. Caenorhabditis elegans, due to its short life cycle, low cost, and convenient genetic manipulation, has become an important model organism for investigating neurodegenerative diseases. Through heterologous expression of amyloid β-protein (Aβ), α-synuclein (α-Syn), mutant superoxide dismutase 1 (SOD1), etc., or constructing mutants using CRISPR/Cas9 gene editing (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9, CRISPR/Cas9), typical pathological features of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) can be reproduced in Caenorhabditis elegans. By integrating RNA interference (RNAi) and compound screening, the Caenorhabditis elegans model has revealed core pathological pathways such as proteostasis, autophagy, and mitochondrial function, and identified multiple potential targets. In the future, relying on the unique strengths of Caenorhabditis elegans in genetic operability, phenotypic quantification, and screening scale, combined with cross-species validation using multiple models, a more predictive and translatable degenerative disease research and intervention system is expected to be established.

Key words: Caenorhabditis elegans, Degenerative diseases, Model organism, Neurodegenerative diseases

中图分类号:

R-332

孙涵,郭芃,俞昕何,等. 秀丽隐杆线虫作为退行性疾病模型的分子通路研究进展[J]. 实验动物与比较医学, 2025, 45(6): 738-751. DOI: 10.12300/j.issn.1674-5817.2025.134.

SUN Han,GUO Peng,YU Xinhe,et al. Progress in Caenorhabditis elegans as a Degenerative Disease Model for Molecular Pathways Studying[J]. Laboratory Animal and Comparative Medicine, 2025, 45(6): 738-751. DOI: 10.12300/j.issn.1674-5817.2025.134.

图/表 4

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疾病 Diseases	定义/特征 Definition/Characteristics	秀丽隐杆线虫模型 Caenorhabditis elegans models
杜氏肌营养不良症 Duchenne muscular dystrophy (DMD)	X染色体连锁隐性遗传，肌肉纤维逐渐坏死和假性肥大	dys-1; ace-1^[12]
肢带型肌营养不良 Limb-girdle muscular dystrophy (LGMD)	累及肩胛带与骨盆带，表现为对称性近端肌无力	LS587; giv otIs117^[13]
肌少症 Sarcopenia	衰老引起的骨骼肌质量显著减少，力量减弱	PD2856; PD2859; PD4092^[14];WJA780^[15]
线粒体肌病 Mitochondrial myopathies	线粒体功能障碍引起的骨骼肌病变	dct-1; allo-1^[16]
糖原累积病 Glycogen storage diseases	酶缺陷导致糖原异常积聚，常见于婴幼儿	RT258;VK2882; pwIs50^[17]
视网膜色素变性 Retinitis pigmentosa (RP)	感光细胞退化，以夜盲和视野缩小为早期表现	snrp-200; prp-8^[18]
骨质疏松症 Osteoporosis	骨密度下降，骨小梁破坏，易致脆性骨折	无
马凡综合征 Marfan syndrome	FBN1基因突变致结缔组织发育异常，累及骨、心血管、眼等系统	无
家族黑蒙性痴呆症 Tay-Sachs disease	HEXA基因突变，溶酶体中GM2神经节苷脂异常积聚	无
脊髓小脑性共济失调 Spinocerebellar ataxia	以共济失调为主要表现的常染色体显性遗传病	无
尼曼-皮克病 Niemann-Pick disease	脂类代谢障碍致肝脾大和神经系统损害	无
阿尔茨海默病 Alzheimer's disease (AD)	β淀粉样蛋白沉积和tau蛋白异常磷酸化引起的认知功能持续退化	Aβ₁_-₄₂^[19]
帕金森病 Parkinson's disease (PD)	黑质多巴胺能神经元丢失，表现为震颤、运动迟缓等	P301L；V337M^[20]；A53T^[21]
亨廷顿病 Huntington's disease (HD)	HTT基因CAG重复扩增引起基底节神经元退化，表现为舞蹈样运动和精神症状	HTN-Q150^[22]
肌萎缩侧索硬化 Amyotrophic lateral sclerosis (ALS)	上下运动神经元退化，导致肌肉萎缩、瘫痪	G93A SOD1^[23]
进行性核上性麻痹 Progressive supranuclear palsy	以垂直眼动障碍、姿势不稳和额叶认知障碍为特征的tau蛋白病	无
多发性硬化症 Multiple sclerosis	中枢神经系统白质脱髓鞘，伴随神经功能缺失	无

疾病 Diseases	定义/特征 Definition/Characteristics	秀丽隐杆线虫模型 Caenorhabditis elegans models
杜氏肌营养不良症 Duchenne muscular dystrophy (DMD)	X染色体连锁隐性遗传，肌肉纤维逐渐坏死和假性肥大	dys-1; ace-1^[12]
肢带型肌营养不良 Limb-girdle muscular dystrophy (LGMD)	累及肩胛带与骨盆带，表现为对称性近端肌无力	LS587; giv otIs117^[13]
肌少症 Sarcopenia	衰老引起的骨骼肌质量显著减少，力量减弱	PD2856; PD2859; PD4092^[14];WJA780^[15]
线粒体肌病 Mitochondrial myopathies	线粒体功能障碍引起的骨骼肌病变	dct-1; allo-1^[16]
糖原累积病 Glycogen storage diseases	酶缺陷导致糖原异常积聚，常见于婴幼儿	RT258;VK2882; pwIs50^[17]
视网膜色素变性 Retinitis pigmentosa (RP)	感光细胞退化，以夜盲和视野缩小为早期表现	snrp-200; prp-8^[18]
骨质疏松症 Osteoporosis	骨密度下降，骨小梁破坏，易致脆性骨折	无
马凡综合征 Marfan syndrome	FBN1基因突变致结缔组织发育异常，累及骨、心血管、眼等系统	无
家族黑蒙性痴呆症 Tay-Sachs disease	HEXA基因突变，溶酶体中GM2神经节苷脂异常积聚	无
脊髓小脑性共济失调 Spinocerebellar ataxia	以共济失调为主要表现的常染色体显性遗传病	无
尼曼-皮克病 Niemann-Pick disease	脂类代谢障碍致肝脾大和神经系统损害	无
阿尔茨海默病 Alzheimer's disease (AD)	β淀粉样蛋白沉积和tau蛋白异常磷酸化引起的认知功能持续退化	Aβ₁_-₄₂^[19]
帕金森病 Parkinson's disease (PD)	黑质多巴胺能神经元丢失，表现为震颤、运动迟缓等	P301L；V337M^[20]；A53T^[21]
亨廷顿病 Huntington's disease (HD)	HTT基因CAG重复扩增引起基底节神经元退化，表现为舞蹈样运动和精神症状	HTN-Q150^[22]
肌萎缩侧索硬化 Amyotrophic lateral sclerosis (ALS)	上下运动神经元退化，导致肌肉萎缩、瘫痪	G93A SOD1^[23]
进行性核上性麻痹 Progressive supranuclear palsy	以垂直眼动障碍、姿势不稳和额叶认知障碍为特征的tau蛋白病	无
多发性硬化症 Multiple sclerosis	中枢神经系统白质脱髓鞘，伴随神经功能缺失	无

秀丽隐杆线虫作为退行性疾病模型的分子通路研究进展

Progress in Caenorhabditis elegans as a Degenerative Disease Model for Molecular Pathways Studying

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