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TG-hATXN3 (85Q) Mouse
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TG-hATXN3 (85Q) Mouse
製品名
TG-hATXN3 (85Q) Mouse
製品ID
C001397
系統名
C57BL/6JCya-Tg(hATXN3*85Q)/Cya
背景情報
C57BL/6JCya
状況
このマウス系統を論文で使用する場合は、「TG-hATXN3 (85Q) Mouse（カタログ番号C001397）はサイアジェンから購入しました。」と引用してください。
Other Target Humanized Mouse Models
Disease Animal Models
Neurodegenerative Diseases
製品タイプ
年齢
遺伝子型
性別
数量
標準的な配送方法では、少なくとも3匹のヘテロ接合体キャリアを保証しています。ホモ接合体キャリアや指定された性別の個体の繁殖サービスも利用可能です。
お見積もりについてはこちらまでご連絡ください
Other Target Humanized Mouse Models
Disease Animal Models
Neurodegenerative Diseases
基本情報
検証 Data
関連リソース
基本情報
遺伝子名
遺伝子別名
AT3, JOS, MJD, ATX3, MJD1, SCA3
NCBI ID
染色体
Chr 14
MGI ID
さらに
系統詳細
The ATXN3 gene encodes Ataxin 3, a protein primarily responsible for intracellular protein degradation and involved in various cellular processes including DNA repair and autophagy. The ATXN3 gene is widely expressed in the human brain and other tissues, with particularly high expression levels in the cerebellum and spinal cord [1]. Spinocerebellar Ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is a progressive neurodegenerative disorder characterized clinically by motor coordination impairment (cerebellar ataxia), bulbar, pyramidal, and extrapyramidal dysfunction, and may be accompanied by peripheral neuropathy or ophthalmoplegia [2]. SCA3 is the most common dominantly inherited ataxia, caused by an abnormal expansion of CAG repeat sequences in the ATXN3 gene. This expansion leads to the formation of an elongated polyglutamine (polyQ) domain in the Ataxin 3 protein, subsequently causing protein aggregation and dysfunction of the ubiquitin-proteasome system. Among polyglutamine diseases, the prevalence of SCA3 is second only to Huntington's disease (HD). The number of CAG repeats in the ATXN3 gene of healthy individuals typically ranges from 12 to 44, whereas affected individuals with SCA3 have 56 to 87 repeats. Individuals with 45 to 55 repeats may exhibit incomplete penetrance of SCA3 symptoms. Similar to other polyglutamine diseases, the length of the CAG repeat is negatively correlated with the age of onset and positively correlated with the severity of SCA3 [2-3].
This strain represents a SCA3 disease model generated through transgenic technology, expressing a human ATXN3 gene carrying approximately 85 CAG repeats (Q). The number of CAG repeats (Q) in the human ATXN3 gene in this model is associated with the more severe forms of SCA3. Preliminary research data indicate that 2-month-old TG-hATXN3(85Q) mice exhibit a significant increase in stride width and a shortened latency to fall in the rotarod test, suggesting impairments in motor coordination and activity. Therefore, this strain can be utilized for research on the ubiquitin-proteasome system and the pathogenic mechanisms of SCA3, as well as for the screening, development, and evaluation of targeted therapeutic drugs.
参考文献
Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S, et al. The gene for Machado-Joseph disease maps to human chromosome 14q. Nat Genet. 1993 Jul;4(3):300-4.
Paulson H. Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol. 2012;103:437-49.
McLoughlin HS, Moore LR, Paulson HL. Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiol Dis. 2020 Feb;134:104635.
系統作製戦略
The human ATXN3 gene, containing its complete genomic sequence (from promoter to 3'UTR) and approximately 85 CAG repeats (Q), was integrated into the mouse genome via transgenic (TG) technology.
適用分野
Research on the ubiquitin-proteasome system and the pathological mechanisms of SCA3；
Screening, development, and evaluation of therapeutic drugs for SCA3.
検証 Data
1. Gene Expression
（1）Comparison of expression levels of related strains
（2）Comparison of gender differences
Figure 1. RT-qPCR results of cerebellum, spinal cord, cerebral cortex, liver, and skeletal muscle from 8-week-old homozygous B6-hATXN3 (Product No.: C001398), heterozygous TG-hATXN3 (85Q) (Product No.: C001397), heterozygous B6-TG(ATXN3-84Q), and wild-type (WT) mice.
Data were analyzed using an ordinary one-way ANOVA, *p < 0.05, **p < 0.01, ***p < 0.001; Bars represent mean ± SEM，n=4.
① Human ATXN3 gene was significantly expressed in the cerebellum, spinal cord, cerebral cortex, liver, and skeletal muscle of B6-hATXN3, TG-hATXN3(85Q), and B6-TG(ATXN3-84Q) mice, whereas no human ATXN3 expression was detected in WT mice.
② Mouse Atxn3 gene was significantly expressed in the cerebellum, spinal cord, cerebral cortex, liver, and skeletal muscle of WT, TG-hATXN3(85Q), and B6-TG(ATXN3-84Q) mice, while B6-hATXN3 mice showed no mouse Atxn3 expression. B6-hATXN3 mice have orthotopic replacement of the mouse gene with the human gene, resulting in loss of mouse gene expression, whereas TG-hATXN3(85Q) and B6-TG(ATXN3-84Q) mice were generated by transgenic technology and retain endogenous mouse gene expression.
③ RT-qPCR results indicate successful transcription of the human gene in B6-hATXN3 mice. In some tissues, the expression level of human ATXN3 in B6-TG(ATXN3-84Q) mice was slightly higher than that in TG-hATXN3(85Q) mice.
2. Protein Expression
（1）Comparison of expression levels of related strains
Figure 2. Western Blot results of the cerebellum and spinal cord of 8-week-old male B6-hATXN3 (Product No.: C001398), TG-hATXN3(85Q) (Product No.: C001397), B6-TG(ATXN3 - 84Q) and wild-type (WT) mice.
① According to the detection method provided in the instruction manual of the human-specific antibody reagent, the theoretical molecular weight of ATXN3 is predicted to be 42KD. Due to the high homology of protein sequences between wild-type mice and humans, corresponding bands were detected in WT and humanized mice. Compared with WT, the molecular weight of the target band detected in B6-hATXN3 mice is larger because the amino acid sequence of human ATXN3 (361aa) is longer than that of mouse Atxn3 (355aa).
② Bands appeared around 65-70KD in transgenic mice TG-hATXN3(85Q) and B6-TG(ATXN3-84Q). This is because different numbers of CAG repeat (Q) sequences were introduced into these two types of mice, increasing the molecular weight of the target band. In addition, both transgenic mice are heterozygotes, and bands of human origin (about 65-70KD) and murine origin (about 42KD) can be detected simultaneously. Therefore, the WB results show a double-band characteristic. The band of TG-hATXN3(85Q) mice is slightly higher than that of B6-TG(ATXN3-84Q) mice, but its expression level is slightly lower.
（2）Comparison of gender differences
Figure 3. Western Blot results of the cerebellum and spinal cord of 8-week-old TG-hATXN3(85Q) mice and wild-type (WT) mice.
① Due to the high homology of protein sequences between wild-type mice and humans, corresponding bands were detected in both WT and TG-hATXN3(85Q) mice.
② A band appeared around 70KD in TG-hATXN3(85Q) mice. This is because the human ATXN3 sequence introduced into this strain carries a specific number of CAG repeat (Q) sequences, which leads to an increase in the molecular weight of the target band. In addition, TG-hATXN3(85Q) mice are heterozygotes, allowing the simultaneous detection of bands of human and murine origins, thus exhibiting the characteristic of double bands.
③ There was no significant difference in the expression level of ATXN3 protein between female and male TG-hATXN3(85Q) mice.
3. Gait Test (2-month-old)
（1）Stride Width (2-month-old)
Figure 4. The forelimb and hindlimb stride width in Tg-hATXN3 (85Q) models at 2 months of age during the gait analysis. Statistical comparisons were performed using unpaired t-test; "ns" indicates no significant differences, *p < 0.05, **p < 0.01.
Mouse numbers: TG-hATXN3(85Q) mice, 10 females and 10 males, total 20; Wild-type mice, 12 females and 12 males, total 24; the same applies below.
（2）Left Forelimb/Hindlimb Stride Length (2-month-old)
Figure 5. The left forelimb and hindlimb stride length in Tg-hATXN3 (85Q) models at 2 months of age during the gait analysis. Statistical comparisons were performed using unpaired t-test; "ns" indicates no significant differences.
（3）Right Forelimb/Hindlimb Stride Length (2-month-old)
Figure 6. The right forelimb and hindlimb stride length in Tg-hATXN3 (85Q) models at 2 months of age during the gait analysis. Statistical comparisons were performed using unpaired t-test; "ns" indicates no significant differences.
Indications for stride width and stride length (Summary of Figures 4 to 6): At 2 months of age, male and mixed-sex Tg-hATXN3 (85Q) mice exhibited a significant increase in stride width without corresponding changes in stride length during gait analysis, which may indicate a potential impairment in locomotor coordination.
4. Rotarod Test: Latency to Fall (2-month-old)
Figure 7. The latency to fall in Tg-hATXN3 (85Q) models at 2 months of age during the rotarod test. Statistical comparisons were performed using the Mann–Whitney test; "ns" indicates no significant differences, *p < 0.05, **p < 0.01.
Indications: In female and mixed-sex comparisons, Tg-ATXN3 (85Q) showed a significant decrease in latency to fall on the rotarod test, indicating deficits in locomotor activity and coordination at 2 months old.
5. Gait Test (4-month-old)
（1）Stride Width (4-month-old)
Figure 8. The forelimb/hindlimb stride width in Tg-hATXN3 (85Q) models at 4 months of age during the gait analysis. Statistical comparisons were performed using either an unpaired t-test or Welch’s t-test, depending on variance equality; "ns" indicates no significant differences, *p < 0.05, **p < 0.01.
（2）Left Forelimb/Hindlimb Stride Length (4-month-old)
Figure 9. The left forelimb and hindlimb stride length in Tg-hATXN3 (85Q) models at 4 months of age during the gait analysis. Statistical comparisons were performed using unpaired t-tests for normally distributed data and the Mann–Whitney test for non-normally distributed data; "ns" indicates no significant differences.
（3）Right Forelimb/Hindlimb Stride Length (4-month-old)
Figure 10. The right forelimb/hindlimb stride length in Tg-hATXN3 (85Q) models at 4 months of age during the gait analysis. Statistical comparisons were performed using unpaired t-tests for normally distributed data and the Mann–Whitney test for non-normally distributed data; "ns" indicates no significant differences.
Indications for stride width and stride length (Summary of Figures 8 to 10): Tg-hATXN3 (85Q) exhibited a significant increase in forelimb stride width with no change in stride length, suggesting impairments in locomotor coordination during gait analysis at 4 months of age.
6. Rotarod Test: Latency to Fall (4-month-old)
Figure 11. The latency to fall in Tg-hATXN3 (85Q) models at 4 months of age during the rotarod test. Statistical comparisons were performed using Mann-Whitney test；**p < 0.01, ***p < 0.001, ****p < 0.0001.
Indications: In both sex-specific and sex-mixed comparisons, Tg-ATXN3 (85Q) mice exhibited a significant reduction in latency to fall during the rotarod test, indicating deficits in locomotor activity and coordination at 4 months of age. The differences between WT mice and Tg-ATXN3 (85Q) mice seemed to increase at 4 months of age compared to those at 2 months.
7. Phenotypic Comparison of B6-hATXN3 and TG-hATXN3(85Q) Mice
a. B6-hATXN3 Mice (Catalog Number: C001398)
The B6-hATXN3 model at 2 and 4 months of age exhibited stable locomotor balance during gait analysis and the rotarod test, comparable to WT mice.
b. TG-hATXN3(85Q) Mice (Catalog Number: C001397)
Tg-hATXN3 (85Q) demonstrated progressive impairments in locomotor balance in both gait analysis and the rotarod test at 2 and 4 months of age.
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