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Establishment of a humanized SCA2 mouse model carrying a CAA disruption preventing CAG repeat expansion in pathogenic
Yao Zhang1,2,3, Yufei Li2, Lin Zhang4
1School of Pharmaceutical Sciences, Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, China.
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 transmission, with no CAG repeat expansion observed in 64 parent-to-offspring transmissions. Compared with SCA2-Q23 mice, SCA2-Q73 mice exhibited progressive motor impairment, reduced Purkinje cell count and volume (indicative of cell atrophy), and muscle atrophy. These observations in the mice suggest that the behavioral and neuropathological 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 differences 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.
Insights
Researchers developed a stable mouse model for Spinocerebellar ataxia type 2 (SCA2) by preventing CAG repeat instability. This model shows disease-relevant motor and muscle atrophy, aiding SCA2 research.
Area of Science:
- Neurogenetics
- Molecular Biology
- Animal Models
Background:
- Spinocerebellar ataxia type 2 (SCA2) is a heterogeneous neurodegenerative disorder caused by expanded CAG repeats in the ATXN2 gene.
- CAG repeat instability in current animal models hinders accurate research into SCA2 pathogenesis.
Purpose of the Study:
- To establish a novel mouse model for SCA2 that exhibits stable CAG repeat transmission across generations.
- To characterize the behavioral and neuropathological phenotypes of this new SCA2 mouse model.
Main Methods:
- Generated a humanized ATXN2 cDNA mouse model with stable 73 CAG repeat expansions (SCA2-Q73) and a control (SCA2-Q23) using Rosa26 locus insertion.
- Assessed CAG repeat stability over 64 parent-to-offspring transmissions.
- Evaluated motor function, Purkinje cell counts, and muscle mass.
- Performed RNA-sequencing on gastrocnemius muscle at 16 and 56 weeks.
Main Results:
- CAG repeat numbers remained stable across all transmissions, confirming the model's genetic stability.
- SCA2-Q73 mice displayed progressive motor deficits, reduced Purkinje cell numbers, and muscle atrophy compared to SCA2-Q23 controls.
- Significant alterations in muscle differentiation and development gene expression, including Myf6, were observed in aged SCA2-Q73 mice.
Conclusions:
- The developed mouse model provides a stable platform for studying SCA2, overcoming limitations of microsatellite instability.
- The model's phenotypes suggest that lack of long-term neural stimulation contributes to muscle atrophy in SCA2.
