肌萎缩侧索硬化症小鼠模型研究进展

doi:10.12300/j.issn.1674-5817.2024.161

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (3): 290-299.DOI: 10.12300/j.issn.1674-5817.2024.161

肌萎缩侧索硬化症小鼠模型研究进展

罗莲莲¹, 袁艳春², 王俊岭², 时广森¹^,³()()

^1.遵义医科大学, 珠海 519000
^2.中南大学湘雅医院神经内科, 长沙 410008
^3.中科中山药物创新研究院, 中山 528400

收稿日期:2024-11-04 修回日期:2025-02-13 出版日期:2025-07-07 发布日期:2025-06-25
通讯作者: 时广森（1986—），男，博士，研究员，研究方向：神经药理学。E-mail： shiguangsen@zidd.ac.cn。ORCID： 0000-0002-9027-6806
作者简介:罗莲莲（1999—），女，硕士研究生，研究方向：ALS小鼠模型构建。E-mail： 15875683769@163.com
基金资助:
国家自然科学基金资助项目“Kinesins相关变异介导Cargo结合紊乱、轴突转运异常在ALS发病机制中的研究”(82171431)

Advances in Mouse Models of Amyotrophic Lateral Sclerosis

LUO Lianlian¹, YUAN Yanchun², WANG Junling², SHI Guangsen¹^,³()()

^1.Zunyi Medical University, Zhuhai 519000, China
^2.Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
^3.Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan 528400, China

Received:2024-11-04 Revised:2025-02-13 Published:2025-06-25 Online:2025-07-07
Contact: SHI Guangsen (ORCID:0000-0002-9027-6806), E-mail: shiguangsen@zidd.ac.cn

摘要/Abstract

摘要：

肌萎缩侧索硬化症（amyotrophic lateral sclerosis，ALS）是一种不可逆的致死性神经退行性疾病，其发病率与人口老龄化进程呈正相关。ALS以运动神经元的渐进性丧失为特征，导致患者肌肉无力、萎缩直至呼吸衰竭。ALS的致病机制涉及遗传和环境等多种因素，其中遗传因素尤为重要。目前已发现多个与ALS相关的致病基因，如铜锌超氧化物歧化酶1编码基因（Cu/Zn superoxide dismutase，Cu/Zn SOD1，又称SOD1）、转录反应DNA结合蛋白43编码基因（transactive response DNA-binding protein 43，TDP-43）、肉瘤融合蛋白基因（fused in sarcoma，FUS）、9号染色体开放阅读框72基因（chromosome open reading frame 72，C9orf72）等，这些基因的突变不仅见于家族性ALS中，也在散发性ALS中被发现。基于发现的ALS风险基因，通过多种方式建立了ALS动物模型，如转基因模型、基因敲入或敲除模型和腺相关病毒过表达模型，这些模型模拟了包括运动神经元丢失、泛素化包涵体形成及神经肌肉接头退变等人类ALS部分典型病理特征，但这些模型仍存在局限性：（1）单一基因突变模型难以全面模拟临床上散发性ALS的复杂多因子致病特征；（2）模式动物与人类在神经退行性疾病的微环境调节机制和病变速率上存在明显差异，这可能影响疾病表型的准确重现和药物效果的评估。为更全面地研究ALS的病理机制并推动有效药物的研发，构建和优化ALS疾病动物模型显得尤为关键。本综述归纳常用的ALS基因突变小鼠模型，分析各类基因修饰小鼠模型的表型和病理特征，包括常见转基因、基因点突变敲入、基因敲除以及通过腺相关病毒载体介导的过表达小鼠模型等；通过对比上述模型的优缺点，进一步讨论了其在ALS病理机制研究和药物开发中的具体应用情况，以期为ALS研究的模型选择提供参考。

关键词: 肌萎缩侧索硬化症, 神经退行性疾病, 遗传因素, 基因突变, 小鼠模型

Abstract:

Amyotrophic lateral sclerosis (ALS) is an irreversible, fatal neurodegenerative disorder whose incidence is positively correlated with the aging population. ALS is characterized by the progressive loss of motor neurons, leading to muscle weakness, atrophy, and ultimately respiratory failure. The pathogenesis of ALS involves multiple factors, including genetic and environmental influences, with genetic factors playing a particularly significant role. To date, several causative genes have been identified in ALS, such as the Cu/Zn superoxide dismutase 1 (Cu/Zn SOD1, also known as SOD1) gene, transactive response DNA-binding protein 43 (TDP-43) gene, fused in sarcoma (FUS) gene, and chromosome open reading frame 72 (C9orf72). Mutations in these genes have been found not only in familial ALS but also in sporadic ALS. Based on the identified ALS risk genes, various ALS animal models have been established through multiple approaches, including transgenic models, gene knockout/knock-in models, and adeno-associated virus-mediated overexpression models. These models simulate some typical pathological features of human ALS, such as motor neuron loss, ubiquitinated inclusions, and neuromuscular junction degeneration. However, these models still have limitations: (1) single-gene mutation models are insufficient to fully replicate the complex multi-factorial pathogenesis of sporadic ALS; (2) significant differences in microenvironmental regulation mechanisms and the rate of neurodegeneration between model organisms and humans may affect the accurate reproduction of disease phenotypes and the reliable evaluation of drug efficacy. To better understand the pathogenesis of ALS and promote the development of effective therapies, constructing and optimizing ALS animal models is crucial. This review aims to summarize commonly used ALS gene mutation mouse models, analyze their phenotypes and pathological characteristics, including transgenic mouse models, gene knockout/knock-in mouse models, and adeno-associated virus-mediated overexpression mouse models, and further discuss their specific applications in ALS pathogenesis research and drug development by comparing the advantages and limitations of each model.

Key words: Amyotrophic lateral sclerosis, Neurodegenerative diseases, Genetic factors, Genetic mutations, Mouse models

中图分类号:

R-332

罗莲莲,袁艳春,王俊岭,等. 肌萎缩侧索硬化症小鼠模型研究进展[J]. 实验动物与比较医学, 2025, 45(3): 290-299. DOI: 10.12300/j.issn.1674-5817.2024.161.

LUO Lianlian,YUAN Yanchun,WANG Junling,et al. Advances in Mouse Models of Amyotrophic Lateral Sclerosis[J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 290-299. DOI: 10.12300/j.issn.1674-5817.2024.161.

图/表 1

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肌萎缩侧索硬化症小鼠模型 ALS mouse model	基因 Gene	氨基酸改变 Amino acid substitution	机制 Mechanism	瘫痪 Paralysis	认知异常 Cognitive impairment	神经元丢失 Neuron loss	神经胶质增生 Gliosis	胞质包涵体 Cytoplasmic inclusion bodies	参考文献 References
转基因小鼠模型 Transgenic mouse model	hSOD1	WT	-	√	-	√	√	SOD1, VAC	[81]
	hSOD1	D90A	-	-	-	√	√	SOD1, VAC	[82]
	hSOD1	G93A	GOF	-	√	√	-	-	[83]
	hTDP-43	WT	-	√	-	√	√	TDP-43, UBI	[32]
	TDP-43	A315T	GOF	-	√	-	√	TDP-43, UBI	[34]
	hTDP-43	Q331K	LOF/GOF	-	-	√	√	×	[31]
	hTDP-43	M337V	GOF	-	-	√	√	×	[31]
	hFUS	WT	GOF	-	√	×	×	×	[84]
	hFUS	R521C	GOF	-	√	-	√	×	[84]
	hFUS	R521C	GOF	√	-	√	√	×	[38]
	hFUS	ΔNLS	GOF	√	-	√	√	FUS	[40]
	hC9orf72	[500] n	GOF	√	√	√	√	DPR, RNA foci, TDP-43	[47]
	hC9orf72	[500] n	-	-	√	×	√	DPR, RNA foci	[85]
	hC9orf72	[500] n	-	-	-	√	√	RNA foci	[48]
基因敲入小鼠模型 Knock-in mouse model	TDP-43	N390D	GOF	-	-	√	√	TDP-43	[57]
	TDP-43	Q331K	GOF	×	√	√	-	×	[55]
	FUS	P517L	GOF	-	-	√	√	FUS	[86]
	FUS	Δ14	GOF	-	-	√	√	FUS	[86]
	FUS	ΔNLS	-	-	-	√	-	FUS	[87]
	C9orf72	(GR)400或(PR)400	-	-	-	√	×	DPR	[88]
	CLCC1	K298A	LOF	-	-	√	-	TDP-43, UBI	[52]
	PCDHA9	L700P	-	√	-	√	√	TDP-43	[53]
腺相关病毒过表达小鼠模型 Adeno-associated virus-mediated overexpression mouse model	TDP-43	WT	-	√	-	√	-	-	[76]
	TDP-43	M337V	GOF	√	-	√	√	TDP-43	[75]
	C9orf72	[66] n	GOF	√	√	√	√	DPR, RNA foci, TDP-43	[71]
	C9orf72	[149] n	GOF	√	√	√	√	DPR, RNA foci, TDP-43	[71]
	C9orf72	[100] n	LOF	×	√	√	√	TDP-43	[89]
	SARM1	V184G	-	√	-	-	-	-	[78]

肌萎缩侧索硬化症小鼠模型 ALS mouse model	基因 Gene	氨基酸改变 Amino acid substitution	机制 Mechanism	瘫痪 Paralysis	认知异常 Cognitive impairment	神经元丢失 Neuron loss	神经胶质增生 Gliosis	胞质包涵体 Cytoplasmic inclusion bodies	参考文献 References
转基因小鼠模型 Transgenic mouse model	hSOD1	WT	-	√	-	√	√	SOD1, VAC	[81]
	hSOD1	D90A	-	-	-	√	√	SOD1, VAC	[82]
	hSOD1	G93A	GOF	-	√	√	-	-	[83]
	hTDP-43	WT	-	√	-	√	√	TDP-43, UBI	[32]
	TDP-43	A315T	GOF	-	√	-	√	TDP-43, UBI	[34]
	hTDP-43	Q331K	LOF/GOF	-	-	√	√	×	[31]
	hTDP-43	M337V	GOF	-	-	√	√	×	[31]
	hFUS	WT	GOF	-	√	×	×	×	[84]
	hFUS	R521C	GOF	-	√	-	√	×	[84]
	hFUS	R521C	GOF	√	-	√	√	×	[38]
	hFUS	ΔNLS	GOF	√	-	√	√	FUS	[40]
	hC9orf72	[500] n	GOF	√	√	√	√	DPR, RNA foci, TDP-43	[47]
	hC9orf72	[500] n	-	-	√	×	√	DPR, RNA foci	[85]
	hC9orf72	[500] n	-	-	-	√	√	RNA foci	[48]
基因敲入小鼠模型 Knock-in mouse model	TDP-43	N390D	GOF	-	-	√	√	TDP-43	[57]
	TDP-43	Q331K	GOF	×	√	√	-	×	[55]
	FUS	P517L	GOF	-	-	√	√	FUS	[86]
	FUS	Δ14	GOF	-	-	√	√	FUS	[86]
	FUS	ΔNLS	-	-	-	√	-	FUS	[87]
	C9orf72	(GR)400或(PR)400	-	-	-	√	×	DPR	[88]
	CLCC1	K298A	LOF	-	-	√	-	TDP-43, UBI	[52]
	PCDHA9	L700P	-	√	-	√	√	TDP-43	[53]
腺相关病毒过表达小鼠模型 Adeno-associated virus-mediated overexpression mouse model	TDP-43	WT	-	√	-	√	-	-	[76]
	TDP-43	M337V	GOF	√	-	√	√	TDP-43	[75]
	C9orf72	[66] n	GOF	√	√	√	√	DPR, RNA foci, TDP-43	[71]
	C9orf72	[149] n	GOF	√	√	√	√	DPR, RNA foci, TDP-43	[71]
	C9orf72	[100] n	LOF	×	√	√	√	TDP-43	[89]
	SARM1	V184G	-	√	-	-	-	-	[78]

肌萎缩侧索硬化症小鼠模型研究进展

Advances in Mouse Models of Amyotrophic Lateral Sclerosis

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