DOI: 10.1002/ame2.70047
Establishment of a humanized SCA2 mouse model carrying a CAA disruption preventing CAG repeat expansion in pathogenic genes
Yao Zhang1
Yufei Li2
Lin Zhang3
Zhaoqing Li4
Keqin Lin2
Kai Huang2
Zhaoqing Yang2
Shaohui Ma2
Hao Sun2
Xiaochao Zhang5
1.School of Pharmaceutical Sciences,Yunnan Key Laboratory of Pharmacology for Natural Products,Kunming Medical University,Kunming,China;Department of Medical Genetics,Institute of Medical Biology,Chinese Academy of Medical Sciences&Peking Union Medical College,Kunming,China;Department of Reproductive Genetics,Hebei General Hospital,Shijiazhuang,China2.Department of Medical Genetics,Institute of Medical Biology,Chinese Academy of Medical Sciences&Peking Union Medical College,Kunming,China3.Department of Pathology,People's Hospital of Qianxinan Prefecture,Xingyi,China4.Department of Medical Genetics,Institute of Medical Biology,Chinese Academy of Medical Sciences&Peking Union Medical College,Kunming,China;School of Life Sciences,Yunnan University,Kunming,China5.School of Pharmaceutical Sciences,Yunnan Key Laboratory of Pharmacology for Natural Products,Kunming Medical University,Kunming,China;Yunnan College of Modern Biomedical Industry,Kunming,China
摘要：Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion of CAG repeats disrupts the genetic stability of animal models,which is detrimental to disease research.
Methods:In this study,we established a mouse model in which CAG repeats do not undergo microsatellite instability(MSI)across generations.A humanized ATXN2 cDNA with four CAA interruptions within 73 CAG expansions was inserted into the Rosa26 locus of C57BL/6J mice.A 23 CAG control mouse model was also generated to verify ATXN2 integration and expression.
Results:In our model,the number of CAG repeats remained stable during transmis-sion,with no CAG repeat expansion observed in 64 parent-to-offspring transmissions.Compared with SCA2-Q23 mice,SCA2-Q73 mice exhibited progressive motor impair-ment,reduced Purkinje cell count and volume(indicative of cell atrophy),and muscle atrophy.These observations in the mice suggest that the behavioral and neuropatho-logical phenotypes may reflect the features of SCA2 patients.RNA-seq analysis of the gastrocnemius muscle in SCA2-Q73 mice showed significant changes in muscle differentiation and development gene expression at 56 weeks,with no significant dif-ferences at 16 weeks compared to SCA2-Q23 mice.The expression level of the Myf6 gene significantly changed in the muscles of aged mice.
Conclusion:In summary,the establishment of this model not only provides a stable animal model for studying CAG transmission in SCA2 but also indicates that the lack of long-term neural stimulation leads to muscle atrophy.
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论文发表日期：2025-09-30
在线出版日期：2025-10-28（本平台首次上网日期，不代表文献的发表时间）
页数：11( 1677-1687 )
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