The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme
Abstract
:1. Introduction
2. Methods
2.1. Subjects
2.2. Tissue Isolation for Western Blot
2.3. Preparation of Samples for Western Blots
2.4. Western Blotting
2.5. Plasmid and Lentivirus Generation
2.6. Cell Culture
2.7. PDE Assay
2.8. Ocular Physiology Studies
2.9. Assessment of Cataracts
2.10. Sleep Studies
2.11. Subcellular Localization
2.12. Statistical Analysis
3. Results
3.1. Western Blots Identify PDE11A4 Protein in Whole-Eye Tissue and Individual Eye Segments
3.2. PDE11A4 Expression in the Eye Changes with Age in A Segment-Specific Manner
3.3. PDE11A4-Y727C and -M878V Variants Exhibit Reduced cAMP-PDE and cGMP-PDE Activity in Neural Cells
3.4. Loss of PDE11A Does Not Alter Eye Growth
3.5. Pde11a Deletion Minimally Improves Sleep Quality
3.6. PDE11A4-Y727C and -M878V Variants Dramatically Alter the Subcellular Compartmentalization of the Enzyme
3.7. The Y727C Variant Dictates Localization of mPDE11A4-WT When Co-Expressed
3.8. The Effects of the Y727C and M878V Variants on PDE11A4 Subcellular Compartmentalization Do Not Require Phosphorylation of S162 nor Dephosphorylation of S117/S124
3.9. The Effects of Y727C on PDE11A4 Subcellular Compartmentalization Are Due to the Loss of the Tyrosine Impacting Processing via the Trans-Golgi Network
4. Discussion
4.1. PDE11A4 Expression Is Greatly Enriched in the Retina vs. Anterior or Posterior Segments of the Eye
4.2. PDE11A4 Expression in the Eye Changes with Age in a Segment-Specific Manner
4.3. The PDE11A4-Y727C and -M878V Variants Impair cAMP Hydrolysis More So than cGMP Hydrolysis
4.4. PDE11A4-Y727C May Reflect a Gain-of-Function Mutation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Batch | Segment | Sex | Acetone | Sample Concentration for Western Blot (µg/µL) |
---|---|---|---|---|
1 | Anterior | male | yes | 2.6 |
2 | Anterior | female | no | 2.32 |
3 | Anterior | male | no | 2.6 |
4 | Anterior | female | no | 2.44 |
1 | Posterior | male | yes | 3 |
2 | Posterior | female | no | 2.72 |
3 | Posterior | male | no | 3 |
4 | Posterior | female | no | 3 |
1 | Retina | male | yes | 2.44 |
2 | Retina | female | no | 2.44 |
3 | Retina | male | no | 2.6 |
4 | Retina | female | no | 2.44 |
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Sbornova, I.; van der Sande, E.; Milosavljevic, S.; Amurrio, E.; Burbano, S.D.; Das, P.K.; Do, H.H.; Fisher, J.L.; Kargbo, P.; Patel, J.; et al. The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme. Cells 2023, 12, 2839. https://doi.org/10.3390/cells12242839
Sbornova I, van der Sande E, Milosavljevic S, Amurrio E, Burbano SD, Das PK, Do HH, Fisher JL, Kargbo P, Patel J, et al. The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme. Cells. 2023; 12(24):2839. https://doi.org/10.3390/cells12242839
Chicago/Turabian StyleSbornova, Irina, Emilie van der Sande, Snezana Milosavljevic, Elvis Amurrio, Steven D. Burbano, Prosun K. Das, Helen H. Do, Janet L. Fisher, Porschderek Kargbo, Janvi Patel, and et al. 2023. "The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme" Cells 12, no. 24: 2839. https://doi.org/10.3390/cells12242839
APA StyleSbornova, I., van der Sande, E., Milosavljevic, S., Amurrio, E., Burbano, S. D., Das, P. K., Do, H. H., Fisher, J. L., Kargbo, P., Patel, J., Porcher, L., De Zeeuw, C. I., Meester-Smoor, M. A., Winkelman, B. H. J., Klaver, C. C. W., Pocivavsek, A., & Kelly, M. P. (2023). The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme. Cells, 12(24), 2839. https://doi.org/10.3390/cells12242839