This modulates SERCA’s conformation to accelerate its function, allowing for increased calcium transport from the cytoplasm to the ER (endoplasmic reticulum) selectively in cells having disrupted calcium balance. Cellular stress pathways are effectively turned off, and the cell returns to a healthy state.
When SERCA is impaired, calcium flow into the ER is reduced, leading to misfolded proteins from the calcium imbalance
The UPR is activated to help clear misfolded proteins, but a prolonged UPR can lead to cell dysfunction and even cell death.
Calcium in cells, while inconspicuous, is the backbone of health. Disturbance of normal calcium levels triggers the ER stress pathway that leads to cell dysfunction, encompassing impaired signaling, respiration, and protein processing. This drives the progression of many diseases.
At Neurodon, our research works to increase the transport of cellular calcium to restore calcium homeostasis and relieve compromising cellular stress pathways. By targeting the source of this stress, we aim to provide disease-modifying effects that slow down the progression of diseases.
The benefit of calcium equilibrium can be seen in the following disease states:
Calcium in Diabetes
Calcium in Parkinson’s
Loss of calcium homeostasis and ER stress via dysfunctional SERCA is a known contributor of damage to dopaminergic neurons in the substantia nigra (SN), the site of Parkinson’s in the brain. Differences in calcium signaling leads to increased susceptibility of SN neurons and cell death.
Calcium in Alzheimer’s
Calcium in DMD
Jacobson, D. A., & Shyng, S.-L. (2019, August 30). Ion channels of the islets in type 2 diabetes. Journal of Molecular Biology. Retrieved July 13, 2022, from https://www.sciencedirect.com/science/article/abs/pii/S0022283619305236
Klec, C., Ziomek, G., Pichler, M., Malli, R., & Graier, W. F. (2019, December 4). Calcium signaling in ß-cell physiology and pathology: A revisit. International journal of molecular sciences. Retrieved July 13, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940736/
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4. Duchenne muscular dystrophy
Goonasekera, S. A., Lam, C. K., Millay, D. P., Sargent, M. A., Hajjar, R. J., Kranias, E. G., & Molkentin, J. D. (2011, March). Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. The Journal of clinical investigation. Retrieved July 13, 2022, from https://pubmed.ncbi.nlm.nih.gov/21285509/
JM, G. (1996, March). Membrane abnormalities and Ca homeostasis in muscles of the MDX mouse, an animal model of the Duchenne muscular dystrophy: A Review. Acta physiologica Scandinavica. Retrieved July 13, 2022, from https://pubmed.ncbi.nlm.nih.gov/8729700/
Loboda, A., & Dulak, J. (2020, July 20). Muscle and cardiac therapeutic strategies for Duchenne Muscular Dystrophy: Past, present, and future – pharmacological reports. SpringerLink. Retrieved July 13, 2022, from https://link.springer.com/article/10.1007/s43440-020-00134-x
Hetz, C. (2012, January 18). The unfolded protein response: Controlling cell fate decisions under ER stress and beyond. Nature News. Retrieved July 13, 2022, from https://www.nature.com/articles/nrm3270