Advances in Mouse Models of Amyotrophic Lateral Sclerosis

doi:10.12300/j.issn.1674-5817.2024.161

Abstract

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

CLC Number:

R-332

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.

Figures/Tables 1

References 89

[1]	WANG H, GUAN L P, DENG M. Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy[J]. Front Neurosci, 2023, 17:1170996. DOI:10.3389/fnins.2023.1170996 .
[2]	BROWN R H, AL-CHALABI A. Amyotrophic lateral sclerosis[J]. N Engl J Med, 2017, 377(2):162-172. DOI:10.1056/nejmra 1603471 .
[3]	MEAD R J, SHAN N, JOSEPH REISER H J, et al. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation[J]. Nat Rev Drug Discov, 2023, 22(3): 185-212. DOI:10.1038/s41573-022-00612-2 .
[4]	XU L, CHEN L, WANG S F, et al. Incidence and prevalence of amyotrophic lateral sclerosis in urban China: a national population-based study[J]. J Neurol Neurosurg Psychiatry, 2020, 91(5):520-525. DOI:10.1136/jnnp-2019-322317 .
[5]	FELDMAN E L, GOUTMAN S A, PETRI S, et al. Amyotrophic lateral sclerosis[J]. Lancet, 2022, 400(10360):1363-1380. DOI:10.1016/s0140-6736(22)01272-7 .
[6]	ZHU L H, LI S H, LI X J, et al. Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges[J]. Transl Neurodegener, 2023, 12(1): 46. DOI:10.1186/s40035-023-00377-7 .
[7]	LI C Y, YANG T M, OU R W, et al. Genome-wide genetic links between amyotrophic lateral sclerosis and autoimmune diseases[J]. BMC Med, 2021, 19(1):27. DOI:10.1186/s12916-021-01903-y .
[8]	KIM G, GAUTIER O, TASSONI-TSUCHIDA E, et al. ALS genetics: gains, losses, and implications for future therapies[J]. Neuron, 2020, 108(5):822-842. DOI:10.1016/j.neuron. 2020.08.022 .
[9]	AL-CHALABI A, FANG F, HANBY M F, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data[J]. J Neurol Neurosurg Psychiatry, 2010, 81(12):1324-1326. DOI:10.1136/jnnp.2010.207464 .
[10]	YOUNGER D S, BROWN R H Jr. Amyotrophic lateral sclerosis.[J]. Handb Clin Neurol, 2023, 196: 203-229. DOI:10.1016/B978-0-323-98817-9.00031-4 .
[11]	WEI Q Q, CHEN X P, CHEN Y P, et al. Unique characteristics of the genetics epidemiology of amyotrophic lateral sclerosis in China[J]. Sci China Life Sci, 2019, 62(4):517-525. DOI:10.1007/s11427-018-9453-x .
[12]	ROSEN D R, SIDDIQUE T, PATTERSON D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis[J]. Nature, 1993, 364(6415):59-62. DOI:10.1038/362059a0 .
[13]	PEGGION C, SCALCON V, MASSIMINO M L, et al. SOD1 in ALS: Taking stock in pathogenic mechanisms and the role of glial and muscle cells[J]. Antioxidants, 2022, 11(4):614. DOI:10.3390/antiox11040614 .
[14]	LI H F, WU Z Y. Genotype-phenotype correlations of amyotrophic lateral sclerosis[J]. Transl Neurodegener, 2016, 5:3. DOI:10.1186/s40035-016-0050-8 .
[15]	ZOU Z Y, ZHOU Z R, CHE C H, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis[J]. J Neurol Neurosurg Psychiatry, 2017, 88(7):540-549. DOI:10.1136/jnnp-2016-315018 .
[16]	GURNEY M E, PU H, CHIU A Y, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation[J]. Science, 1994, 264(5166):1772-1775. DOI:10.1126/science.8209258 .
[17]	TODD T W, PETRUCELLI L. Modelling amyotrophic lateral sclerosis in rodents[J]. Nat Rev Neurosci, 2022, 23(4): 231-251. DOI:10.1038/s41583-022-00564-x .
[18]	CIURO M, SANGIORGIO M, LEANZA G, et al. A meta-analysis study of SOD1-mutant mouse models of als to analyse the determinants of disease onset and progression[J]. Int J Mol Sci, 2022, 24(1):216-232. DOI:10.3390/ijms24010216 .
[19]	ACEVEDO-AROZENA A, KALMAR B, ESSA S, et al. A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis[J]. Dis Model Mech, 2011, 4(5):686-700. DOI:10.1242/dmm.007237 .
[20]	LINO M M, SCHNEIDER C, CARONI P. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease[J]. J Neurosci, 2002, 22(12):4825-4832. DOI:10.1523/JNEUROSCI.22-12-04825.2002 .
[21]	SAITOH Y, TAKAHASHI Y. Riluzole for the treatment of amyotrophic lateral sclerosis[J]. Neurodegener Dis Manag, 2020, 10(6):343-355. DOI:10.2217/nmt-2020-0033 .
[22]	BROOKS B R, BERRY J D, CIEPIELEWSKA M, et al. Intravenous edaravone treatment in ALS and survival: an exploratory, retrospective, administrative claims analysis[J]. EClinicalMedicine, 2022, 52:101590. DOI:10.1016/j.eclinm. 2022.101590 .
[23]	MCCAMPBELL A, COLE T, WEGENER A J, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models[J]. J Clin Invest, 2018, 128(8):3558-3567. DOI:10.1172/JCI99081 .
[24]	MACKENZIE I R A, BIGIO E H, INCE P G, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations[J]. Ann Neurol, 2007, 61(5):427-434. DOI:10.1002/ana.21147 .
[25]	DE GIORGIO F, MADURO C, FISHER E M C, et al. Transgenic and physiological mouse models give insights into different aspects of amyotrophic lateral sclerosis[J]. Dis Model Mech, 2019, 12(1): dmm037424. DOI:10.1242/dmm.037424 .
[26]	TSAI K J, YANG C H, FANG Y H, et al. Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U[J]. J Exp Med, 2010, 207(8):1661-1673. DOI:10.1084/jem. 20092164 .
[27]	WATANABE S, OIWA K, MURATA Y, et al. ALS-linked TDP-43^M337V knock-in mice exhibit splicing deregulation without neurodegeneration[J]. Mol Brain, 2020, 13(1):8. DOI:10.1186/s13041-020-0550-4 .
[28]	LANZNASTER D, VEYRAT-DUREBEX C, VOURC'H P, et al. Metabolomics: a tool to understand the impact of genetic mutations in amyotrophic lateral sclerosis[J]. Genes, 2020, 11(5):537. DOI:10.3390/genes11050537 .
[29]	LUTZ C. Mouse models of ALS: past, present and future[J]. Brain Res, 2018, 1693(Pt A):1-10. DOI:10.1016/j.brainres. 2018.03.024 .
[30]	CHAN G, VAN HUMMEL A, VAN DER HOVEN J, et al. Neurodegeneration and motor deficits in the absence of astrogliosis upon transgenic mutant TDP-43 expression in mature mice[J]. Am J Pathol, 2020, 190(8):1713-1722. DOI:10.1016/j.ajpath.2020.04.009 .
[31]	ARNOLD E S, LING S C, HUELGA S C, et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43[J]. Proc Natl Acad Sci USA, 2013, 110(8): E736-E745. DOI:10.1073/pnas.1222809110 .
[32]	WILS H, KLEINBERGER G, JANSSENS J, et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration[J]. Proc Natl Acad Sci USA, 2010, 107(8): 3858-3863. DOI:10.1073/pnas.0912417107 .
[33]	HERDEWYN S, CIRILLO C, VAN DEN BOSCH L, et al. Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T) mice[J]. Mol Neurodegener, 2014, 9:24. DOI:10.1186/1750-1326-9-24 .
[34]	SWARUP V, PHANEUF D, BAREIL C, et al. Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments[J]. Brain, 2011, 134(Pt 9):2610-2626. DOI:10.1093/brain/awr159 .
[35]	MEJZINI R, FLYNN L L, PITOUT I L, et al. ALS genetics, mechanisms, and therapeutics: where are we now?[J]. Front Neurosci, 2019, 13:1310. DOI:10.3389/fnins.2019.01310 .
[36]	CHEN C, DING X F, AKRAM N, et al. Fused in sarcoma: properties, self-assembly and correlation with neurodegenerative diseases[J]. Molecules, 2019, 24(8):1622. DOI:10.3390/molecules24081622 .
[37]	PELAEZ M C, DESMEULES A, GELON P A, et al. Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition[J]. Acta Neuropathol Commun, 2023, 11(1): 182. DOI:10.1186/s40478-023-01671-1 .
[38]	QIU H Y, LEE S, SHANG Y L, et al. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects[J]. J Clin Invest, 2021, 131(7): e149564. DOI:10.1172/JCI149564 .
[39]	MITCHELL J C, MCGOLDRICK P, VANCE C, et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion[J]. Acta Neuropathol, 2013, 125(2):273-288. DOI:10.1007/s00401-012-1043-z .
[40]	SHIIHASHI G, ITO D, YAGI T, et al. Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice[J]. Brain, 2016, 139(Pt 9):2380-2394. DOI:10.1093/brain/aww161 .
[41]	SHIIHASHI G, ITO D, ARAI I, et al. Dendritic homeostasis disruption in a novel frontotemporal dementia mouse model expressing cytoplasmic fused in sarcoma[J]. EBioMedicine, 2017, 24:102-115. DOI:10.1016/j.ebiom.2017.09.005 .
[42]	DEBRAY S, RACE V, CRABBÉ V, et al. Frequency of C9orf72 repeat expansions in amyotrophic lateral sclerosis: a Belgian cohort study[J]. Neurobiol Aging, 2013, 34(12):2890.e7-2892890.e12. DOI:10.1016/j.neurobiolaging.2013.06.009 .
[43]	PARAMESWARAN J, ZHANG N, BRAEMS E, et al. Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS[J]. elife, 2023, 12:e85902. DOI:10.7554/eLife.85902 .
[44]	BABIĆ LEKO M, ŽUPUNSKI V, KIRINCICH J, et al. Molecular mechanisms of neurodegeneration related to C9orf72 hexanucleotide repeat expansion[J]. Behav Neurol, 2019, 2019:2909168. DOI:10.1155/2019/2909168 .
[45]	NGUYEN H P, VAN BROECKHOVEN C, VAN DER ZEE J. ALS genes in the genomic era and their implications for FTD[J]. Trends Genet, 2018, 34(6):404-423. DOI:10.1016/j.tig. 2018. 03.001 .
[46]	BECKERS J, THARKESHWAR A K, VAN DAMME P. C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels[J]. Autophagy, 2021, 17(11):3306-3322. DOI:10.1080/15548627. 2021.1872189 .
[47]	LIU Y J, PATTAMATTA A, ZU T, et al. C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD[J]. Neuron, 2016, 90(3):521-534. DOI:10.1016/j.neuron.2016.04.005 .
[48]	NGUYEN L, MONTRASIO F, PATTAMATTA A, et al. Antibody therapy targeting RAN proteins rescues C9 ALS/FTD phenotypes in C9orf72 mouse model[J]. Neuron, 2020, 105(4):645-662.e11. DOI:10.1016/j.neuron.2019.11.007 .
[49]	MORDES D A, MORRISON B M, AMENT X H, et al. Absence of survival and motor deficits in 500 repeat C9ORF72 BAC mice[J]. Neuron, 2020, 108(4):775-783.e4. DOI:10.1016/j.neuron. 2020.08.009 .
[50]	NGUYEN L, LABOISSONNIERE L A, GUO S, et al. Survival and motor phenotypes in FVB C9-500 ALS/FTD BAC transgenic mice reproduced by multiple labs[J]. Neuron, 2020, 108(4):784-796.e3. DOI:10.1016/j.neuron.2020.09.009 .
[51]	RICH K A, PINO M G, YALVAC M E, et al. Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant[J]. Neurobiol Dis, 2023, 182:106148. DOI:10.1016/j.nbd.2023.106148 .
[52]	GUO L, MAO Q L, HE J, et al. Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies[J]. Cell Res, 2023, 33(7): 497-515. DOI:10.1038/s41422-023-00798-z .
[53]	ZHONG J, WANG C D, ZHANG D, et al. PCDHA9 as a candidate gene for amyotrophic lateral sclerosis[J]. Nat Commun, 2024, 15(1):2189. DOI:10.1038/s41467-024-46333-5 .
[54]	LÉPINE S, NAULEAU-JAVAUDIN A, DENEAULT E, et al. Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons[J]. iScience, 2024, 27(3):109166. DOI:10.1016/j.isci.2024.109166 .
[55]	WHITE M A, KIM E, DUFFY A, et al. TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD[J]. Nat Neurosci, 2018, 21(4):552-563. DOI:10.1038/s41593-018-0113-5 .
[56]	EBSTEIN S Y, YAGUDAYEVA I, SHNEIDER N A. Mutant TDP-43 causes early-stage dose-dependent motor neuron degeneration in a TARDBP knockin mouse model of ALS[J]. Cell Rep, 2019, 26(2):364-373.e4. DOI:10.1016/j.celrep. 2018.12.045 .
[57]	HUANG S L, WU L S, LEE M, et al. A robust TDP-43 knock-in mouse model of ALS[J]. Acta Neuropathol Commun, 2020, 8(1):3. DOI:10.1186/s40478-020-0881-5 .
[58]	KOROBEYNIKOV V A, LYASHCHENKO A K, BLANCO-REDONDO B, et al. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis[J]. Nat Med, 2022, 28(1):104-116. DOI:10.1038/s41591-021-01615-z .
[59]	DEVOY A, KALMAR B, STEWART M, et al. Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice[J]. Brain, 2017, 140(11):2797-2805. DOI:10.1093/brain/awx248 .
[60]	DENG Z Q, LIM J, WANG Q, et al. ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway[J]. Autophagy, 2020, 16(5):917-931. DOI:10.1080/15548627.2019.1644076 .
[61]	BURBERRY A, WELLS M F, LIMONE F, et al. C9orf72 suppresses systemic and neural inflammation induced by gut bacteria[J]. Nature, 2020, 582(7810):89-94. DOI:10.1038/s41586-020-2288-7 .
[62]	ZHU Q, JIANG J, GENDRON T F, et al. Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72[J]. Nat Neurosci, 2020, 23(5):615-624. DOI:10.1038/s41593-020-0619-5 .
[63]	POLLOCK N, MACPHERSON P C, STAUNTON C A, et al. Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and neuromuscular junctions in mice[J]. eNeuro, 2023, 10(3):ENEURO.0086-22.2023. DOI:10.1523/ENEURO.0086-22.2023 .
[64]	SHEFNER J M, REAUME A G, FLOOD D G, et al. Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy[J]. Neurology, 1999, 53(6):1239-1246. DOI:10.1212/wnl.53.6.1239 .
[65]	YOSHIHARA D, FUJIWARA N, KITANAKA N, et al. The absence of the SOD1 gene causes abnormal monoaminergic neurotransmission and motivational impairment-like behavior in mice[J]. Free Radic Res, 2016, 50(11):1245-1256. DOI:10.1080/10715762.2016.1234048 .
[66]	KRAEMER B C, SCHUCK T, WHEELER J M, et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis[J]. Acta Neuropathol, 2010, 119(4):409-419. DOI:10.1007/s00401-010-0659-0 .
[67]	KINO Y, WASHIZU C, KUROSAWA M, et al. FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis[J]. Acta Neuropathol Commun, 2015, 3:24. DOI:10.1186/s40478-015-0202-6 .
[68]	KURASHIGE T, KURAMOCHI M, OHSAWA R, et al. Optineurin defects cause TDP43-pathology with autophagic vacuolar formation[J]. Neurobiol Dis, 2021, 148:105215. DOI:10.1016/j.nbd.2020.105215 .
[69]	GURFINKEL Y, POLAIN N, SONAR K, et al. Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis[J]. Neurobiol Dis, 2022, 174:105859. DOI:10.1016/j.nbd.2022.105859 .
[70]	RAMESH BABU J, LAMAR SEIBENHENER M, PENG J M, et al. Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration[J]. J Neurochem, 2008, 106(1):107-120. DOI:10.1111/j.1471-4159. 2008.05340.x .
[71]	CHEW J, COOK C, GENDRON T F, et al. Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy[J]. Mol Neurodegener, 2019, 14(1):9. DOI:10.1186/s13024-019-0310-z .
[72]	GENDRON T F, BIENIEK K F, ZHANG Y J, et al. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS[J]. Acta Neuropathol, 2013, 126(6): 829-844. DOI:10.1007/s00401-013-1192-8 .
[73]	COOK C N, WU Y W, ODEH H M, et al. C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy[J]. Sci Transl Med, 2020, 12(559): eabb3774. DOI:10.1126/scitranslmed.abb3774 .
[74]	ZHANG Y J, GENDRON T F, GRIMA J C, et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins[J]. Nat Neurosci, 2016, 19(5):668-677. DOI:10.1038/nn.4272 .
[75]	YAN S, WANG C E, WEI W J, et al. TDP-43 causes differential pathology in neuronal versus glial cells in the mouse brain[J]. Hum Mol Genet, 2014, 23(10):2678-2693. DOI:10.1093/hmg/DDT662 .
[76]	TSUBOGUCHI S, NAKAMURA Y, ISHIHARA T, et al. TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models[J]. Acta Neuropathol, 2023, 146(4): 611-629. DOI:10.1007/s00401-023-02615-8 .
[77]	JACKSON K L, DAYTON R D, DEVERMAN B E, et al. Better targeting, better efficiency for wide-scale neuronal transduction with the synapsin promoter and AAV-PHP.B[J]. Front Mol Neurosci, 2016, 9:116. DOI:10.3389/fnmol. 2016. 00116 .
[78]	JOSEPH BLOOM A, MAO X R, STRICKLAND A, et al. Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients[J]. Mol Neurodegener, 2022, 17(1): 1-15. DOI:10.1186/s13024-021-00511-x .
[79]	VAN HUMMEL A, SABALE M, PRZYBYLA M, et al. TDP-43 pathology and functional deficits in wild-type and ALS/FTD mutant cyclin F mouse models[J]. Neuropathol Appl Neurobiol, 2023, 49(2): e12902. DOI:10.1111/nan.12902 .
[80]	YIN P, BAI D Z, DENG F Y, et al. SQSTM1-mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain[J]. Autophagy, 2022, 18(8):1955-1968. DOI:10.1080/15548627.2021.2013653 .
[81]	GRAFFMO K S, FORSBERG K, BERGH J, et al. Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis[J]. Hum Mol Genet, 2013, 22(1):51-60. DOI:10.1093/hmg/dds399 .
[82]	ANDREAS JONSSON P, GRAFFMO K S, BRÄNNSTRÖM T, et al. Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1[J]. J Neuropathol Exp Neurol, 2006, 65(12):1126-1136. DOI:10.1097/01.jnen.0000248545.36046.3c .
[83]	QUARTA E, BRAVI R, SCAMBI I, et al. Increased anxiety-like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS mouse model[J]. J Comp Neurol, 2015, 523(11):1622-1638. DOI:10.1002/cne.23759 .
[84]	LÓPEZ-ERAUSKIN J, TADOKORO T, BAUGHN M W, et al. ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS[J]. Neuron, 2020, 106(2):354. DOI:10.1016/j.neuron. 2020.04.006 .
[85]	PATTAMATTA A, NGUYEN L, OLAFSON H R, et al. Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice[J]. Hum Mol Genet, 2021, 29(24):3900-3918. DOI:10.1093/hmg/ddaa279 .
[86]	KOROBEYNIKOV V A, LYASHCHENKO A K, BLANCO-REDONDO B, et al. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis[J]. Nat Med, 2022, 28(1):104-116. DOI:10.1038/s41591-021-01615-z .
[87]	PICCHIARELLI G, DEMESTRE M, ZUKO A, et al. FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis[J]. Nat Neurosci, 2019, 22(11):1793-1805. DOI:10.1038/s41593-019-0498-9 .
[88]	MILIOTO C, CARCOLÉ M, GIBLIN A, et al. PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons[J]. Nat Neurosci, 2024, 27(4):643-655. DOI:10.1038/s41593-024-01589-4 .
[89]	ZHANG Y J, GENDRON T F, EBBERT M T W, et al. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis[J]. Nat Med, 2018, 24(8):1136-1142. DOI:10.1038/s41591-018-0071-1 .

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]