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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2015

Open Access 01-12-2015 | Review

CRISPR/Cas9: a powerful genetic engineering tool for establishing large animal models of neurodegenerative diseases

Authors: Zhuchi Tu, Weili Yang, Sen Yan, Xiangyu Guo, Xiao-Jiang Li

Published in: Molecular Neurodegeneration | Issue 1/2015

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Abstract

Animal models are extremely valuable to help us understand the pathogenesis of neurodegenerative disorders and to find treatments for them. Since large animals are more like humans than rodents, they make good models to identify the important pathological events that may be seen in humans but not in small animals; large animals are also very important for validating effective treatments or confirming therapeutic targets. Due to the lack of embryonic stem cell lines from large animals, it has been difficult to use traditional gene targeting technology to establish large animal models of neurodegenerative diseases. Recently, CRISPR/Cas9 was used successfully to genetically modify genomes in various species. Here we discuss the use of CRISPR/Cas9 technology to establish large animal models that can more faithfully mimic human neurodegenerative diseases.
Literature
1.
2.
3.
Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. The Lancet. 2011;377(9769):942–55.CrossRef
4.
Ribeiro FM, Camargos ER, Souza LC, Teixeira AL. Animal models of neurodegenerative diseases. Rev Bras Psiquiatr. 2013;35 Suppl 2:S82–91.PubMedCrossRef
5.
6.
Gusella JF, MacDonald ME, Ambrose CM, Duyao MP. Molecular genetics of Huntington's disease. Arch Neurol. 1993;50(11):1157–63.PubMedCrossRef
7.
Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993;4(4):398–403.PubMedCrossRef
8.
9.
Van Den Bosch L. Genetic rodent models of amyotrophic lateral sclerosis. J Biomed Biotechnol. 2011;2011:348765.CrossRef
10.
Hoke A, Ray M. Rodent models of chemotherapy-induced peripheral neuropathy. ILAR J. 2014;54(3):273–81.PubMedCrossRef
11.
Babin PJ, Goizet C, Raldua D. Zebrafish models of human motor neuron diseases: Advantages and limitations. Progr Neurobiol. 2014;118:36–58.CrossRef
12.
Angela Cenci M, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nature. 2002;3:6.
13.
Li XJ, Li S. Large Animal Models of Huntington's Disease. Curr Top Behav Neurosci. 2015;22:149–60.PubMedCrossRef
14.
Hayden MR, Goldblatt J, Wallis G, Winship IM, Beighton P. Molecular genetics and Huntington's disease. The South African situation. S Afr Med J. 1987;71(11):683–6.PubMed
15.
Crook ZR, Housman D. Huntington's disease: can mice lead the way to treatment? Neuron. 2011;69(3):423–35.PubMedCrossRef
16.
Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, et al. Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron. 2012;74(6):1031–44.PubMedCentralPubMedCrossRef
17.
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. Cell. 1996;87:14.
18.
Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J Neurosci. 1999;19(8):3248–57.PubMed
19.
Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet. 2003;12(13):1555–67.PubMedCrossRef
20.
Gray M, Shirasaki DI, Cepeda C, Andre VM, Wilburn B, Lu XH, et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci. 2008;28(24):6182–95.PubMedCentralPubMedCrossRef
21.
Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, et al. Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Mol Genet. 1999;8(1):115–22.PubMedCrossRef
22.
Wheeler VC, White JK, Gutekunst CA, Vrbanac V, Weaver M, Li XJ, et al. Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum Mol Genet. 2000;9(4):503–13.PubMedCrossRef
23.
Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999;8(3):397–407.PubMedCrossRef
24.
Hodgson JG, Agopyan N, Gutekunst C-A, Leavitt BR, LePiane F, Singaraja R, et al. A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron. 1999;23(1):181–92.PubMedCrossRef
25.
Yang D, Wang CE, Zhao B, Li W, Ouyang Z, Liu Z, et al. Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet. 2010;19(20):3983–94.PubMedCentralPubMedCrossRef
26.
Mielcarek M, Inuabasi L, Bondulich MK, Muller T, Osborne GF, Franklin SA, et al. Dysfunction of the CNS-heart axis in mouse models of Huntington's disease. PLoS Genetics. 2014;10(8):e1004550.PubMedCentralPubMedCrossRef
27.
Uchida M, Shimatsu Y, Onoe K, Matsuyama N, Niki R, Ikeda JE, et al. Production of transgenic miniature pigs by pronuclear microinjection. Transgenic Res. 2001;10(6):577–82.PubMedCrossRef
28.
Baxa M, Hruska-Plochan M, Juhas S, Vodicka P, Pavlok A, Juhasova J, et al. A transgenic minipig model of Huntington's Disease. J Huntingtons Dis. 2013;2(1):47–68.PubMed
29.
Jacobsen JC, Bawden CS, Rudiger SR, McLaughlan CJ, Reid SJ, Waldvogel HJ, et al. An ovine transgenic Huntington's disease model. Hum Mol Genet. 2010;19(10):1873–82.PubMedCentralPubMedCrossRef
30.
31.
Garriga-Canut M, Agustin-Pavon C, Herrmann F, Sanchez A, Dierssen M, Fillat C, et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A. 2012;109(45):E3136–45.PubMedCentralPubMedCrossRef
32.
Mitsumoto H, Hanson MR, Chad DA. Amyotrophic lateral sclerosis. Recent advances in pathogenesis and therapeutic trials. Arch Neurol. 1988;45(2):189–202.PubMedCrossRef
33.
Louvel E, Hugon J, Doble A. Therapeutic advances in amyotrophic lateral sclerosis. Trends Pharmacol Sci. 1997;18(6):196–203.PubMedCrossRef
34.
Ayach L, Curti C, Montana M, Pisano P, Vanelle P. Amyotrophic lateral sclerosis: update on etiological treatment. Therapie. 2013;68(2):93–106.PubMedCrossRef
35.
Joyce PI, Fratta P, Fisher EMC, Acevedo-Arozena A. SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm Genome. 2011;22(7–8):420–48.PubMedCrossRef
36.
Schmucker S, Puccio H. Understanding the molecular mechanisms of Friedreich Ataxia to develop therapeutic approaches. Hum Mol Genet. 2010;19(R1):R103–10
37.
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–3.PubMedCrossRef
38.
Hargus G, Ehrlich M, Hallmann AL, Kuhlmann T. Human stem cell models of neurodegeneration: a novel approach to study mechanisms of disease development. Acta Neuropathol. 2014;127(2):151–73.PubMedCrossRef
39.
40.
Migheli A, Atzori C, Piva R, Tortarolo M, Girelli M, Schiffer D, et al. Lack of apoptosis in mice with ALS. Nat Med. 1999;5(9):966–7.PubMedCrossRef
41.
Cleveland DW, Rothstein JD. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci. 2001;2(11):806–19.PubMedCrossRef
42.
Barrett EF, Barrett JN, David G. Mitochondria in motor nerve terminals: function in health and in mutant superoxide dismutase 1 mouse models of familial ALS. J Bioenerg Biomembr. 2011;43(6):581–6.PubMedCentralPubMedCrossRef
43.
Sondergaard LV, Ladewig J, Dagnaes-Hansen F, Herskin MS, Holm IE. Object recognition as a measure of memory in 1–2 years old transgenic minipigs carrying the APPsw mutation for Alzheimer's disease. Transgenic Res. 2012;21(6):1341–8.PubMedCrossRef
44.
Chan AWS, Chong KY, Martinovich C, Simerly C, Schatten G. Transgenic monkeys produced by retroviral gene transfer into mature oocytes. Science. 2001;291(5502):309–12.PubMedCrossRef
45.
Nasir J. Transgenic monkey raises hope for primate models of human diseases. Clin Genet. 2001;59(5):304–5.PubMedCrossRef
46.
Senior K. What next after the first transgenic monkey? Lancet. 2001;357(9254):450
47.
Yang SH, Cheng PH, Banta H, Piotrowska-Nitsche K, Yang JJ, Cheng EC, et al. Towards a transgenic model of Huntington's disease in a non-human primate. Nature. 2008;453(7197):921–4.PubMedCentralPubMedCrossRef
48.
Niu Y, Guo X, Chen Y, Wang CE, Gao J, Yang W, et al. Early Parkinson's disease symptoms in α-synuclein transgenic monkeys. Hum Mol Genet. 2014;24(8):2308–17.
49.
Parkinson J. An essay on the shaking palsy. 2014.
50.
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. science. 1997;276(5321):2045–47.
51.
Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatr. 2008;79(4):368–76.PubMedCrossRef
52.
Bugos O, Bhide M, Zilka N. Beyond the rat models of human neurodegenerative disorders. Cell Mol Neurobiol. 2009;29(6–7):859–69.PubMedCrossRef
53.
Schwarting R, Huston J. The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Progr Neurobiol. 1996;50(2):275–331.CrossRef
54.
55.
56.
Yang W, Wang G, Wang C-E, Guo X, Yin P, Gao J, et al. Mutant alpha-synuclein causes Age-dependent neuropathology in monkey brain. J Neurosci. 2015;35(21):8345–58.PubMedCrossRef
57.
Cho SW, Kim S, Kim JM, Kim JS. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat Biotechnol. 2013;31(3):230–2.PubMedCrossRef
58.
59.
Mali P, Aach J, Stranges PB, Esvelt KM, Moosburner M, Kosuri S, et al. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol. 2013;31(9):833–8.PubMedCrossRef
60.
61.
Shan Q, Wang Y, Li J, Zhang Y, Chen K, Liang Z, et al. Targeted genome modification of crop plants using a CRISPR-Cas system. Nat Biotech. 2013;31(8):686–8.CrossRef
62.
63.
Zhou X, Xin J, Fan N, Zou Q, Huang J, Ouyang Z, et al. Generation of CRISPR/Cas9-mediated gene-targeted pigs via somatic cell nuclear transfer. Cell Mol Life Sci. 2015;72(6):1175–84.PubMedCrossRef
64.
Niu Y, Shen B, Cui Y, Chen Y, Wang J, Wang L, et al. Generation of Gene-Modified Cynomolgus Monkey via Cas9/RNA-Mediated Gene Targeting in One-Cell Embryos. Cell. 2014;156(4):836–43.PubMedCrossRef
65.
Chen Y, Zheng Y, Kang Y, Yang W, Niu Y, Guo X, et al. Functional disruption of the dystrophin gene in rhesus monkey using CRISPR/Cas9. Hum Mol Genet. 2015;24(13):3764–74.PubMed
66.
Chen Y, Cui Y, Shen B, Niu Y, Zhao X, Wang L, et al. Germline acquisition of Cas9/RNA-mediated gene modifications in monkeys. Cell Res. 2015;25(2):262–5.PubMedCrossRef
67.
Wan H, Feng C, Teng F, Yang S, Hu B, Niu Y, et al. One-step generation of p53 gene biallelic mutant Cynomolgus monkey via the CRISPR/Cas system. Cell Res. 2015;25(2):258–61.PubMedCrossRef
68.
Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326(5959):1509–12.PubMedCrossRef
69.
Christian M, Cermak T, Doyle EL, Schmidt C, Zhang F, Hummel A, et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics. 2010;186(2):757–61.PubMedCentralPubMedCrossRef
70.
Wei C, Liu J, Yu Z, Zhang B, Gao G, Jiao R. TALEN or Cas9 - rapid, efficient and specific choices for genome modifications. J Genet Genomics. 2013;40(6):281–9.PubMedCrossRef
71.
72.
73.
74.
75.
Yen ST, Zhang M, Deng JM, Usman SJ, Smith CN, Parker-Thornburg J, et al. Somatic mosaicism and allele complexity induced by CRISPR/Cas9 RNA injections in mouse zygotes. Dev Biol. 2014;393(1):3–9.PubMedCentralPubMedCrossRef
76.
Long CZ, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science. 2014;345(6201):1184–8.PubMedCentralPubMedCrossRef
77.
78.
Cros D, Harnden P, Pellissier JF, Serratrice G. Muscle hypertrophy in Duchenne muscular dystrophy. A pathological and morphometric study. J Neurol. 1989;236(1):43–7.PubMedCrossRef
79.
Tsao CY, Bartolo C, Luquette MH, Mendell JR, Prior TW. A novel mechanism for the expression of dystrophin in a Duchenne muscular dystrophy patient. Neurology. 1996;46(2):12002–2.
80.
Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol. 2015;33(5):538–42.PubMedCrossRef
81.
Sung YH, Kim JM, Kim HT, Lee J, Jeon J, Jin Y, et al. Highly efficient gene knockout in mice and zebrafish with RNA-guided endonucleases. Genome Res. 2014;24(1):125–31.PubMedCentralPubMedCrossRef
82.
Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell. 2013;154(6):1380–9.PubMedCentralPubMedCrossRef
83.
Chu VT, Weber T, Wefers B, Wurst W, Sander S, Rajewsky K, et al. Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol. 2015;33(5):543–8.PubMedCrossRef
84.
85.
86.
Metadata
Title
CRISPR/Cas9: a powerful genetic engineering tool for establishing large animal models of neurodegenerative diseases
Authors
Zhuchi Tu
Weili Yang
Sen Yan
Xiangyu Guo
Xiao-Jiang Li
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-015-0031-x

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