Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons
Abstract
:1. Introduction
2. Materials and Methods
2.1. iPSC Line Establishment and Culture
2.2. SOD1G85R iPSC Site-Specific Correction by CRISPR/Cas9-Mediated Homologous Recombination
2.3. Robust MN Differentiation from iPSCs
2.4. Immunocytochemistry (ICC) Staining and Nerve Fiber Density/Beads Calculations
2.5. Calcium Imaging
2.6. ALS Animal Model and Small Compound Treatment
2.7. Animal Motor Behavior Test
2.8. Western Blotting
2.9. RNA-Microarray and Analysis
2.10. Statistical Analysis
3. Results
3.1. Generation of SOD1G85R ALS and SOD1G85G Isogenic iPSCs, and Robust MN Differentiation via the CHSF Method
3.2. NF Aggregates and Nerve Fiber Degeneration in SOD1 ALS MNs
3.3. Gastrodin Reduces NF Aggregates and Promotes Nerve Fiber Extension in SOD1 ALS MNs
3.4. Gastrodin Reverses the Glutamate Induced Hyper-Calcium Flux in SOD1 ALS MNs
3.5. Gastrodin Rescues Nerve Fiber Cytopathies in Sporadic ALS MNs As Well As Restoring Motor Performance and Prolonging Survival in ALS Mice
3.6. Gastrodin Activates the IGF-1 Signaling Pathway and GSK3β Activity to Rescue Nerve Fiber Cytopathies in SOD1 ALS MNs
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Ting, H.-C.; Yang, H.-I.; Harn, H.-J.; Chiu, I.-M.; Su, H.-L.; Li, X.; Chen, M.-F.; Ho, T.-J.; Liu, C.-A.; Tsai, Y.-J.; et al. Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons. Cells 2021, 10, 2773. https://doi.org/10.3390/cells10102773
Ting H-C, Yang H-I, Harn H-J, Chiu I-M, Su H-L, Li X, Chen M-F, Ho T-J, Liu C-A, Tsai Y-J, et al. Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons. Cells. 2021; 10(10):2773. https://doi.org/10.3390/cells10102773
Chicago/Turabian StyleTing, Hsiao-Chien, Hui-I Yang, Horng-Jyh Harn, Ing-Ming Chiu, Hong-Lin Su, Xiang Li, Mei-Fang Chen, Tsung-Jung Ho, Ching-Ann Liu, Yung-Jen Tsai, and et al. 2021. "Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons" Cells 10, no. 10: 2773. https://doi.org/10.3390/cells10102773