Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3
Abstract
:1. Introduction
2. Results
2.1. IP3R2 Expression in the CMVMJD135 Mouse Model
2.2. The Double Mutant Mice Show Progressive Neurological Deficits Similar to CMVMJD135 Animals
3. Discussion
4. Materials and Methods
4.1. Animal Generation and Maintenance
4.2. Molecular Analysis: Macrodissection, RNA Isolation, cDNA Synthesis, and Real-Time Quantitative PCR Analysis
4.3. Behavior Analysis
4.3.1. Motor Swimming Test
4.3.2. Beam Balance Test
4.3.3. Adhesive Removal Test
4.3.4. Hanging Wire Grid Test
4.3.5. Wire Maneuver Test
4.4. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Appendix A
Itpr1 | One-way ANOVA, with Tukey HSD comparisons F (3,24) = 0.399, p = 0.755 WT vs. Q135 p = 0.990 WT vs. IP3R2 KO p = 0.999 Q135 vs. IP3R2; Q135 p = 0.706 | n (WT) = 8 n (Q135) = 9 n (IP3R2 KO) = 3 n (IP3R2; Q135) = 5 |
Itpr2 | One-way ANOVA, with Dunnett T3 comparisons F (3,24) = 7.888, p = 0.001 WT vs. Q135 p = 1.000 WT vs. IP3R2 KO p = 0.027 Q135 vs. IP3R2; Q135 p < 0.001 | n (WT) = 8 n (Q135) = 9 n (IP3R2 KO) = 3 n (IP3R2; Q135) = 5 |
CAG number | Independent t-test t (15,10) = −0.080, p = 0.937 | n (Q135) = 6 n (IP3R2; Q135) = 11 |
Body Weight | Repeated Measures ANOVA, with Tukey HSD comparisons Within-subjects effect | F (10,82) = 12.596, p < 0.001 np2 = 0.604 Between-subjects effect | F (4,33) = 18.178, p < 0.001 np2 = 0.688 WT vs. Q135 p = 0.043 WT vs. IP3R2 KO p = 0.960 WT vs. IP3R2 HET p = 0.991 Q135 vs. IP3R2; Q135 p = 0.008 | n (WT) = 12 n (Q135) = 9 n (IP3R2 KO) = 10 n (IP3R2; HET) = 6 n (IP3R2; Q135) = 12 |
One-way ANOVA, with Tukey HSD comparisons Week 12 F (4,48) = 11.075, p ≤ 0.001 WT vs. Q135 p = 0.005 WT vs. IP3R2 KO p = 0.734 WT vs. IP3R2 HET p = 0.790 Q135 vs. IP3R2; Q135 p = 0.342 Week 16 F (4,48) = 12.052, p ≤ 0.001 WT vs. Q135 p = 0.018 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 0.986 Q135 vs. IP3R2; Q135 p = 0.426 Week 20 F (4,47) = 28.619, p ≤ 0.001 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 0.950 WT vs. IP3R2 HET p = 0.996 Q135 vs. IP3R2; Q135 p = 0.133 Week 24 F (4,47) = 34.103, p ≤ 0.001 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 0.894 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.085 Week 30 F (4,41) = 30.343, p ≤ 0.001 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.076 | ||
Motor Swimming test | Repeated Measures ANOVA, with Tukey HSD comparisons Within-subjects effect | F (15,116) = 5.660, p < 0.001 np2 = 0.422 Between-subjects effect | F (4,31) = 10.592, p < 0.001 np2 = 0.577 WT vs. Q135 p = 0.003 WT vs. IP3R2 KO p = 0.960 WT vs. IP3R2 HET p = 0.982 Q135 vs. IP3R2; Q135 p = 0.994 | n (WT) = 12 n (Q135) = 9 n (IP3R2 KO) = 10 n (IP3R2; HET) = 6 n (IP3R2; Q135) = 12 |
One-way ANOVA, with Tukey HSD comparisons Week 12 F (4,48) = 8.573, p ≤ 0.001 WT vs. Q135 p = 0.019 WT vs. IP3R2 KO p = 0.669 WT vs. IP3R2 HET p = 0.102 Q135 vs. IP3R2; Q135 p = 0.307 Week 16 F (4,48) = 6.000, p = 0.001 WT vs. Q135 p = 0.027 WT vs. IP3R2 KO p = 0.999 WT vs. IP3R2 HET p = 0.992 Q135 vs. IP3R2; Q135 p = 1.000 Week 20 F (4,47) = 11.852, p ≤ 0.001 WT vs. Q135 p = 0.002 WT vs. IP3R2 KO p = 0.997 WT vs. IP3R2 HET p = 0.991 Q135 vs. IP3R2; Q135 p = 0.999 Week 24 F (4,45) = 18,597, p ≤ 0.001 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 0.996 WT vs. IP3R2 HET p = 0.600 Q135 vs. IP3R2; Q135 p = 1.000 Week 30 F (4,39) = 13,979, p ≤ 0.001 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 0.999 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.988 | ||
Beam Walking Test 12 mm square (6–20 week) | Repeated Measures ANOVA, with Tukey HSD comparisons Within-subjects effect | F (10,67) = 4.901, p < 0.001 np2 = 0.403 Between-subjects effect | F (4,29) = 13.460, p < 0.001 np2 = 0.650 WT vs. Q135 p = 0.028 WT vs. IP3R2 KO p = 0.784 WT vs. IP3R2 HET p = 0.986 Q135 vs. IP3R2; Q135 p = 0.193 | n (WT) = 12 n (Q135) = 9 n (IP3R2 KO) = 10 n (IP3R2; HET) = 6 n (IP3R2; Q135) = 12 |
One-way ANOVA, with Tukey HSD comparisons Week 12 F (4,44) = 11.955, p < 0.001 WT vs. Q135 p = 0.015 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 0.986 Q135 vs. IP3R2; Q135 p = 0.405 Week 16 F (4,43) = 20.203, p < 0.001 WT vs. Q135 p = 0.063 WT vs. IP3R2 KO p = 0.999 WT vs. IP3R2 HET p = 0.999 Q135 vs. IP3R2; Q135 p = 0.008 Week 20 F (4,38) = 25.265, p < 0.001 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 0.940 WT vs. IP3R2 HET p = 0.971 Q135 vs. IP3R2; Q135 p = 1.000 | ||
Beam Walking Test—12 mm square 24–30 week (Score) | Kruskal–Wallis test 24 week χw2 (4,47) = 28.174 p < 0.001 np2 = 0.585 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.972 30 week χw2 (4,40) = 27.513 p < 0.001 np2 = 0.681 WT vs. Q135 p = 0.002 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.743 | n (WT) = 11 n (Q135) = 9 n (IP3R2 KO) = 10 n (IP3R2; HET) = 6 n (IP3R2; Q135) = 11 |
Beam Walking Test—11 mm circle 6–30 week (Score) | Kruskal–Wallis test 8 week χw2 (4,46) = 16.832 p = 0.002 np2 = 0.329 WT vs. Q135 p = 0.006 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.959 12 week χw2 (4,49) = 29.833 p < 0.001 np2 = 0.596 WT vs. Q135 p = 0.002 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 0.460 Q135 vs. IP3R2; Q135 p = 0.377 16 week χw2 (4,49) = 36.432 p < 0.001 np2 = 0.743 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.560 20 week χw2 (4,48) = 29.218 p < 0.001 np2 = 0.596 WT vs. Q135 p = 0.002 WT vs. IP3R2 KO p = 0.666 WT vs. IP3R2 HET p = 0.710 Q135 vs. IP3R2; Q135 p = 0.907 24 week χw2 (4,47) = 38.818 p < 0.001 np2 = 0.833 WT vs. Q135 p < 0.001 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.387 30 week χw2 (4,41) = 26.704 p < 0.001 np2 = 0.641 WT vs. Q135 p = 0.004 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 0.517 Q135 vs. IP3R2; Q135 p = 0.440 | n (WT) = 12 n (Q135) = 9 n (IP3R2 KO) = 10 n (IP3R2; HET) = 6 n (IP3R2; Q135) = 12 |
Adhesive Removal | Repeated Measures ANOVA, with Tukey HSD comparisons Within-subjects effect | F (10,80) = 4.439, p < 0.001 np2 = 0.350 Between-subjects effect | F (4,33) = 7.379, p < 0.001 np2 = 0.472 WT vs. Q135 p = 0.097 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.788 | n (WT) = 12 n (Q135) = 9 n (IP3R2;KO) = 10 n (IP3R2; HET) = 6 n (IP3R2;Q135) = 12 |
One-way ANOVA, with Tukey HSD comparisons Week 24 F (4,47) = 7.509, p < 0.001 WT vs. Q135 p = 0.044 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.743 Week 30 F (4,41) = 10.509, p < 0.001 WT vs. Q135 p = 0.006 WT vs. IP3R2 KO p = 1.000 WT vs. IP3R2 HET p = 1.000 Q135 vs. IP3R2; Q135 p = 0.983 | ||
Hanging Wire Grid | Kruskal–Wallis test 6 week χw2 (4,49) = 26.873 p < 0.001 np2 = 0.531 WT vs. Q135 p = 0.018 WT vs. IP3R2 KO p = 0.855 WT vs. IP3R2 HET p = 0.637 Q135 vs. IP3R2; Q135 p = 0.199 8 week χw2 (4,46) = 17,550 p = 0.002 np2 = 0.346 WT vs. Q135 p = 0.006 WT vs. IP3R2 KO p = 0.700 WT vs. IP3R2 HET p = 0.761 Q135 vs. IP3R2; Q135 p = 0.871 12 week χw2 (4,49) = 26.969 p < 0.001 np2 = 0.533 WT vs. Q135 p = 0.009 WT vs. IP3R2 KO p = 0.678 WT vs. IP3R2 HET p = 0.718 Q135 vs. IP3R2; Q135 p = 0.391 16 week χw2 (4,49) = 23.184 p < 0.001 np2 = 0.449 WT vs. Q135 p = 0.031 WT vs. IP3R2 KO p = 0.799 WT vs. IP3R2 HET p = 0.813 Q135 vs. IP3R2; Q135 p = 0.201 20 week χw2 (4,48) = 25.962 p < 0.001 np2 = 0.522 WT vs. Q135 p = 0.006 WT vs. IP3R2 KO p = 0.675 WT vs. IP3R2 HET p = 0.920 Q135 vs. IP3R2; Q135 p = 0.282 24 week χw2 (4,48) = 24.298 p < 0.001 np2 = 0.484 WT vs. Q135 p = 0.008 WT vs. IP3R2 KO p = 0.587 WT vs. IP3R2 HET p = 0.459 Q135 vs. IP3R2; Q135 p = 0.719 30 week χw2 (4,42) = 25.541 p < 0.001 np2 = 0.593 WT vs. Q135 p = 0.014 WT vs. IP3R2 KO p = 0.699 WT vs. IP3R2 HET p = 0.883 Q135 vs. IP3R2; Q135 p = 0.444 | n (WT) = 12 n (Q135) = 9 n (IP3R2 KO) = 10 n (IP3R2; HET) = 6 n (IP3R2; Q135) = 12 |
Wire Manouver | Kruskal–Wallis test 6 week χw2 (4,49) = 19.771 p = 0.001 np2 = 0.373 WT vs. Q135 p = 0.011 WT vs. IP3R2 KO p = 0.210 WT vs. IP3R2 HET p = 0.560 Q135 vs. IP3R2; Q135 p = 0.549 12 week χw2 (4,49) = 20.302 p < 0.001 np2 = 0.384 WT vs. Q135 p = 0.020 WT vs. IP3R2 KO p = 0.976 WT vs. IP3R2 HET p = 0.616 Q135 vs. IP3R2; Q135 p = 0.442 16 week χw2 (4,49) = 20.585 p < 0.001 np2 = 0.391 WT vs. Q135 p = 0.004 WT vs. IP3R2 KO p = 0.699 WT vs. IP3R2 HET p = 0.568 Q135 vs. IP3R2; Q135 p = 0.944 | n (WT) = 12 n (Q135) = 9 n (IP3R2 KO) = 10 n (IP3R2; HET) = 6 n (IP3R2; Q135) = 12 |
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Gene | Primer Sequence | |
---|---|---|
Itpr1 | Foward | Reverse |
5′-CTCTGTATGCGGAGGGATCTAC-3′ | 5′-GCGGAGTATCGATTCATAGGAC-3′ | |
Itpr2 | Foward | Reverse |
5′-CTTCCTCTACATTGGGGACATC-3′ | 5′-GGCAGAGTATCGATTCATAGGG-3′ | |
B2m | Foward | Reverse |
5′-CCTTCAGCAAGGACTGGTCT-3′ | 5′-TCTCGATCCCAGTAGACGGT-3′ |
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Cunha-Garcia, D.; Monteiro-Fernandes, D.; Correia, J.S.; Neves-Carvalho, A.; Vilaça-Ferreira, A.C.; Guerra-Gomes, S.; Viana, J.F.; Oliveira, J.F.; Teixeira-Castro, A.; Maciel, P.; et al. Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3. Int. J. Mol. Sci. 2023, 24, 10606. https://doi.org/10.3390/ijms241310606
Cunha-Garcia D, Monteiro-Fernandes D, Correia JS, Neves-Carvalho A, Vilaça-Ferreira AC, Guerra-Gomes S, Viana JF, Oliveira JF, Teixeira-Castro A, Maciel P, et al. Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3. International Journal of Molecular Sciences. 2023; 24(13):10606. https://doi.org/10.3390/ijms241310606
Chicago/Turabian StyleCunha-Garcia, Daniela, Daniela Monteiro-Fernandes, Joana Sofia Correia, Andreia Neves-Carvalho, Ana Catarina Vilaça-Ferreira, Sónia Guerra-Gomes, João Filipe Viana, João Filipe Oliveira, Andreia Teixeira-Castro, Patrícia Maciel, and et al. 2023. "Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3" International Journal of Molecular Sciences 24, no. 13: 10606. https://doi.org/10.3390/ijms241310606