CLINICAL SIGNIFICANCE OF SERC-A DYSFUNCTION: IMPLICATIONS FOR BRAIN FUNCTION IN ALZHEIMER'S DISEASE

Main Article Content

Sadia Sohail
Farheen Anjum
Dr. Muhammad Ismail Khan
Fatima Bibi
Rohma Rehman
Munazza Tariq

Keywords

Alzheimer’s Disease, Calcium-Transporting ATPases, Calcium Metabolism Disorders, N-Methyl-D-Aspartate Receptor, Endoplasmic Reticulum

Abstract

Objective: This review aims to reevaluate the molecular mechanisms of sarcoendoplasmic reticulum Ca2+-dependent ATPase (SERC-A) in Alzheimer's disease and discuss the implications of calcium regulation, particularly in relation to vascular risk and the function of voltage-gated calcium channels.


Methods: We comprehensively analysed existing literature to understand the role of calcium regulation in Alzheimer's disease, focusing on the internal instability of calcium levels and its association with vascular risk. Special attention was given to the molecular mechanisms of SERC-A and the functional aspects of voltage-gated calcium channels.


Results: The prevalence of Alzheimer's disease is influenced by various factors, collectively disrupting normal neuronal functions. Internal instability of calcium levels emerges as a significant factor, with a notable connection to increased vascular risk – a condition prevalent in individuals affected by Alzheimer's disease. This review highlights the molecular intricacies of SERC-A in the disease context and provides insights into the functional significance of voltage-gated calcium channels.


Conclusion: Understanding the regulatory mechanisms of calcium, specifically the role of SERC-A and voltage-gated calcium channels, holds clinical relevance. The irregular function of SERC-A has been implicated in diverse alterations of brain function. Insights from this review may open new avenues for therapeutic alternatives targeting calcium dysregulation in Alzheimer's disease, providing potential interventions to address the underlying causes of neuronal dysfunction.

Abstract 225 | pdf Downloads 61

References

1. Aluja, D., Delgado-Tomás, S., Ruiz-Meana, M., Barrabés, J. A., & Inserte, J. (2022). Calpains as Potential Therapeutic Targets for Myocardial Hypertrophy. International Journal of Molecular Sciences, 23(8), 4103.
2. Alvarez, J. A. E., Jafri, M. S., & Ullah, A. (2023). Local Control Model of a Human Ventricular Myocyte: An Exploration of Frequency-Dependent Changes and Calcium Sparks. Biomolecules, 13(8), 1259.
3. Berna-Erro, A., Ramesh, G., Delgado, E., Corbacho, A. J., Ferrer-Marín, F., Teruel, R., . . . Redondo, P. C. (2023). CAPN1 (Calpain1)-Dependent Cleavage of STIM1 (Stromal Interaction Molecule 1) Results in an Enhanced SOCE (Store-Operated Calcium Entry) in Human Neonatal Platelets. Arteriosclerosis, Thrombosis, and Vascular Biology, 43(5), e151-e170.
4. Collins, H. E., Zhang, D., & Chatham, J. C. (2022). STIM and orai-mediated regulation of calcium signaling in age-related diseases. Frontiers in Aging, 3, 876785.
5. Ednie, A. R., Paul-Onyia, C. D., & Bennett, E. S. (2023). Reduced O-GlcNAcylation diminishes cardiomyocyte Ca2+ dependent facilitation and frequency dependent acceleration of relaxation. Journal of Molecular and Cellular Cardiology, 180, 10-21.
6. Enrich, C., Lu, A., Tebar, F., Rentero, C., & Grewal, T. (2023). Ca2+ and Annexins–Emerging Players for Sensing and Transferring Cholesterol and Phosphoinositides via Membrane Contact Sites Cholesterol and PI (4, 5) P2 in Vital Biological Functions: From Coexistence to Crosstalk (pp. 393-438): Springer.
7. Ferrer, B. J. (2022). Structural and Biophysical Investigation of Calmodulin Binding to the Third Domain of Human Prp40a. Vanderbilt University.
8. Hamilton, S., Terentyeva, R., Veress, R., Perger, F., Nichtova, Z., Martin, B., . . . Terentyev, D. (2023). Ryanodine receptor hyperactivity promotes mitochondrial dysfunction via calpain-dependent OPA1 proteolysis. Biophysical Journal, 122(3), 378a.
9. Hansen, M. S. H. (2023). Calcium dependent arrhythmia mechanisms in CPVT and ischemia-reperfusion.
10. Hussey, J. W., Limpitikul, W. B., & Dick, I. E. (2023). Calmodulin Mutations in Human Disease. Channels, 17(1), 2165278.
11. Irnaten, M., & O’Brien, C. J. (2023). Calcium-Signalling in Human Glaucoma Lamina Cribrosa Myofibroblasts. International Journal of Molecular Sciences, 24(2), 1287.
12. Li, R.-l., Zhuo, C.-l., Yan, X., Li, H., Lin, L., Li, L.-y., . . . Liu, L.-l. (2024). Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs. International Journal of Biological Sciences, 20(2), 680.
13. MacLeod, K. T. (2023). Changes in cellular Ca2+ and Na+ regulation during the progression towards heart failure. The Journal of Physiology, 601(5), 905-921.
14. MacNeil, E. K. (2023). Ca2+-dependent inactivation of a neuronal Ca2+ channel is regulated by intracellular Ca2+ handling.
15. Michalak, M. (2023). Calreticulin: Endoplasmic reticulum Ca2+ gatekeeper. Journal of Cellular and Molecular Medicine.
16. Mitronova, G. Y., Quentin, C., Belov, V. N., Wegener, J. r. W., Kiszka, K. A., & Lehnart, S. E. (2023). 1, 4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities. Journal of Medicinal Chemistry, 66(23), 15761-15775.
17. Nakamura, J., Maruyama, Y., Tajima, G., Hayakawa, S., Suwa, M., & Sato, C. (2023). Ca2+ Dependent Formation/Collapse of Cylindrical Ca2+-ATPase Crystals in Scallop Sarcoplasmic Reticulum (SR) Vesicles: A Possible Dynamic Role of SR in Regulation of Muscle Contraction. International Journal of Molecular Sciences, 24(8), 7080.
18. Nikiforova, A. B., Baburina, Y. L., Borisova, M. P., Surin, A. K., Kharechkina, E. S., Krestinina, O. V., . . . Kruglov, A. G. (2023). Mitochondrial F-ATP Synthase Co-Migrating Proteins and Ca2+-Dependent Formation of Large Channels. Cells, 12(19), 2414.
19. Osman, V., Speigel, I., Patel, K., & Hemmings, H. C. (2023). Isoflurane alters presynaptic endoplasmic reticulum calcium dynamics in wild-type and malignant hyperthermia-susceptible rodent hippocampal neurons. Eneuro, 10(8).
20. Ousingsawat, J., Talbi, K., Gómez-Martín, H., Koy, A., Fernández-Jaén, A., Tekgül, H., . . . Kunzelmann, K. (2023). Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia. Brain, awad412.
21. Pereira, A. C., De Pascale, J., Resende, R., Cardoso, S., Ferreira, I., Neves, B. M., . . . Morais, S. (2022). ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system. Cellular and Molecular Life Sciences, 79(4), 213.
22. Peters, E. C., Gee, M. T., Pawlowski, L. N., Kath, A. M., Polk, F. D., Vance, C. J., . . . Pires, P. W. (2022). Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries. Journal of Cerebral Blood Flow & Metabolism, 42(1), 145-161.
23. Rajeev, P., Singh, N., Kechkar, A., Butler, C., Ramanan, N., Sibarita, J.-B., . . . Nair, D. (2022). Nanoscale regulation of Ca2+ dependent phase transitions and real-time dynamics of SAP97/hDLG. nature communications, 13(1), 4236.
24. Rieder, P. (2023). Glial Ca2+ signaling in the spinal cord and the myelin-protective effect of the GABAb receptor in oligodendrocyte precursor cells.
25. Šeflová, J., Cruz-Cortés, C., Guerrero-Serna, G., Robia, S. L., & Espinoza-Fonseca, L. M. (2023). Mechanisms for cardiac SERCA activation by its substrate and a synthetic allosteric modulator using fluorescence lifetime imaging. PNAS nexus, pgad453.
26. Seitz, A., Busch, M., Kroemer, J., Schneider, A., Simon, S., Jungmann, A., . . . Ritterhoff, J. (2023). S100A1′ s single cysteine is an indispensable redox-switch for the protection against diastolic calcium leakage in cardiomyocytes. bioRxiv, 2023.2009. 2001.555853.
27. Sharma, A., Sari, E., Lee, Y., Patel, S., Brenner, M., Marambaud, P., & Wang, P. (2023). Extracellular CIRP Induces Calpain Activation in Neurons via PLC-IP3-Dependent Calcium Pathway. Molecular Neurobiology, 60(6), 3311-3328.
28. Sun, C.-C., Lee, S.-Y., Chen, L.-H., Lai, C.-H., Shen, Z.-Q., Chen, N.-N., . . . Chiu, W.-T. (2023). Targeting Ca2+-dependent pathways to promote corneal epithelial wound healing induced by CISD2 deficiency. Cellular Signalling, 110755.
29. Takenaka, M., Kodama, M., Murayama, T., Ishigami-Yuasa, M., Mori, S., Ishida, R., . . . Iino, M. (2023a). Screening for novel RyR2 inhibitors by ER Ca2+ monitoring. bioRxiv, 2023.2008. 2021.553510.
30. Takenaka, M., Kodama, M., Murayama, T., Ishigami-Yuasa, M., Mori, S., Ishida, R., . . . Iino, M. (2023b). Screening for Novel Type 2 Ryanodine Receptor Inhibitors by Endoplasmic Reticulum Ca2+ Monitoring. Molecular Pharmacology, 104(6), 275-286.
31. Walters, G. C., & Usachev, Y. M. (2023). Mitochondrial calcium cycling in neuronal function and neurodegeneration. Frontiers in cell and developmental biology, 11, 1094356.
32. Yadav, M. P., Narayanasamy, S., & Aradhyam, G. K. (2023). Structural Plasticity Allows Calumenin-1 to Moonlight as a Ca2+-Independent Chaperone: Pb2+ Enables Probing Alternate Inhibitory Conformation. Biochemistry.
33. Yamasaki, E., Thakore, P., Ali, S., Sanchez Solano, A., Wang, X., Gao, X., . . . Earley, S. (2023). Impaired intracellular Ca2+ signaling contributes to age-related cerebral small vessel disease in Col4a1 mutant mice. Science Signaling, 16(811), eadi3966.
34. Yamasaki, E., Thakore, P., Ali, S., Solano, A. S., Wang, X., Gao, X., . . . Earley, S. Defective Ca2+-dependent activation of TRPM4 channels contributes to age-related cerebral small vessel disease in Col4a1 mutant mice.
35. Yu, W., Zhang, Q., Qiu, Y., Chen, H., Huang, X., Xiao, L., . . . Tong, X. (2023). CDN1163 alleviates SERCA2 dysfunction-induced pulmonary vascular remodeling by inhibiting the phenotypic transition of pulmonary artery smooth muscle cells. Clinical and Experimental Hypertension, 45(1), 2272062.
36. Zampese, E., Wokosin, D. L., Gonzalez-Rodriguez, P., Guzman, J. N., Tkatch, T., Kondapalli, J., . . . Rizzuto, R. (2022). Ca2+ channels couple spiking to mitochondrial metabolism in substantia nigra dopaminergic neurons. Science Advances, 8(39), eabp8701.
37. Zhang, L., Au-Yeung, C.-L., Huang, C., Yeung, T.-L., Ferri-Borgogno, S., Lawson, B. C., . . . Thomas, V. (2022). Ryanodine receptor 1-mediated Ca2+ signaling and mitochondrial reprogramming modulate uterine serous cancer malignant phenotypes. Journal of Experimental & Clinical Cancer Research, 41(1), 1-20.

Most read articles by the same author(s)