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S1R: target protein holds promising potential for treating neurodegenerative diseases

By: Aleena Kuriakose

Highlights:

  • The S1R is a multifunctional protein located in the endoplasmic reticulum.

  • Several studies have shown that S1Rs were involved in higher-ordered brain functions, such as memory and cognitive thinking.

  • S1R agonists have produced a broad range of neuroprotective effects associated with neurological disorders such as Alzheimer’s Disease and Huntington’s Disease.

Pictures are worth a thousand words, but memories are priceless. And being unable to recall them is precisely why neurodegenerative diseases are devastating: you see the pictures but are deaf to the thousand words they screech. However, recent neuropathological research sheds light on a type of protein that raises the hope of brain disorders themselves becoming a faded photograph of the past: Sigma-1 receptors (S1Rs).


Initially misclassified as opioid receptors in the mid-1970s, S1Rs are now recognized as multifunctional, chaperone proteins situated in the endoplasmic reticulum (ER). They have a wide variety of functions including regulating ER stress and protein folding - processes that when abnormal are associated with many neurological diseases such as Alzheimer’s Disease, Huntington’s Disease, and other forms of dementia.


Most importantly, the S1R exhibits neuroprotective properties as a chaperone protein when it is activated. Dr. Eduardo Benarroch, a professor of neurology at Mayo Clinic, has suggested that S1R agonists, or substances that initiate a response when binded to a receptor (in this case, the S1R), could offer a combination approach to dementia symptoms. He writes, “Research over the last few years has shown that acting on the S1R pathway could hold therapeutic promise in the treatment of symptoms associated with dementia...Unlike the majority of existing pharmacological interventions, sigma-1 agonists could address underlying disease pathology to improve symptoms.” Dr. Benarroch further explains the significance of S1R agonists, which could potentially save neurons and decelerate disease progression, hence limiting dementia symptoms.


In a study titled, “Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor,” researchers demonstrated how ER stress stimulates S1R expression through one of the cell’s responses to ER stress via the S1R agonist fluvoxamine, producing effects such as repressing cell death signaling. Fluvoxamine has high affinity toward the S1R, and is a selective serotonin reuptake inhibitor (SSRI). SSRIs are typically used as antidepressants for depression disorders, but in this case, fluvoxamine activates the S1R in neuroblastoma cells, preventing neuronal cell death from ER stress, suggesting how S1R agonists could be used as a plausible therapy for cerebral diseases caused by ER stress.


While S1R offers numerous opportunities in the field of neuropathology, the molecular functions that govern them as well as the processes surrounding brain pathology are still poorly understood and require further scientific investigation. Linda Nguyen, MD, PhD, of the University of California, San Diego cites a lack of evidence: “Further work is needed to characterize the potential for using sigma-1 receptor ligands to slow the progression of neurodegeneration and/or reverse an existing pathology...Clarifying the cellular mechanisms and molecular targets of sigma-1 receptors in the [central nervous system] will also be critical to understanding the physiological roles and pathological alterations of sigma-1 receptors.”


However, the current and ongoing research illustrates how S1Rs are extraordinarily interesting: they represent a relatively new field of research as complex pharmacological chaperones and could pave the way for novel methods for treating dementia as a therapeutic target. As researchers try to address the underlying questions and clarify the molecular mechanisms of S1Rs and brain disorders, we become one step closer to preventing dementia and memory decline.


  1. Chaperone proteins: One of the most powerful systems regulating protein folding and aggregation - involved in ER stress and protein homeostasis

  2. ER stress: When the capacity of the ER to fold proteins becomes saturated


References:

Omi, T., Tanimukai, H., Kanayama, D. et al. Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor. Cell Death Dis 5, e1332 (2014). https://doi.org/10.1038/cddis.2014.301

Pass, W. (2019, April 23). Sigma-1 Agonists Offer Combination Approach to Dementia Symptoms.



Ryskamp, D. A., Korban, S., Zhemkov, V., Kraskovskaya, N., & Bezprozvanny, I. (2019, July 31). Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases. Frontiers. https://www.frontiersin.org/articles/10.3389/fnins.2019.00862/full#h4.



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