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Cell. 2018 May 3;173(4):989-1002.e13. doi: 10.1016/j.cell.2018.03.005. Epub 2018 Mar 29.

A Huntingtin Knockin Pig Model Recapitulates Features of Selective Neurodegeneration in Huntington's Disease.

Author information

1
Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632 Guangzhou, China.
2
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China.
3
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Department of Neurology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080 Guangdong, China.
5
College of Animal Science and Technology, Yunnan Agricultural University, 650201 Kunming, China.
6
Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632 Guangzhou, China; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: sli@emory.edu.
7
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell, Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China; Jilin Provincial Key Laboratory of Animal Embryo Engineering, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, 130062 Changchun, China. Electronic address: lai_liangxue@gibh.ac.cn.
8
Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, 510632 Guangzhou, China; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: xli2@emory.edu.

Abstract

Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable. More importantly, brains of HD KI pig display striking and selective degeneration of striatal medium spiny neurons. Thus, using a large animal model of HD, we demonstrate for the first time that overt and selective neurodegeneration seen in HD patients can be recapitulated by endogenously expressed mutant proteins in large mammals, a finding that also underscores the importance of using large mammals to investigate the pathogenesis of neurodegenerative diseases and their therapeutics.

KEYWORDS:

CRISPR/Cas9; huntingtin; knockin; large animal; neurodegeneration; polyglutamine; striatum

PMID:
29606351
PMCID:
PMC5935586
DOI:
10.1016/j.cell.2018.03.005
[Indexed for MEDLINE]
Free PMC Article

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