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The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases.
Curr Neuropharmacol. 2018; 16(1):97-116.CN

Abstract

BACKGROUND

Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death.

METHODS

Research articles on Sigma-1 receptor were reviewed.

RESULTS

ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins.

CONCLUSION

Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity.

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Authors+Show Affiliations

Penke B
University of Szeged, Department of Medical Chemistry, Faculty of Medicine, Szeged, Hungary.
Fulop L
University of Szeged, Department of Medical Chemistry, Faculty of Medicine, Szeged, Hungary.
Szucs M
University of Szeged, Department of Medical Chemistry, Faculty of Medicine, Szeged, Hungary.
Frecska E
University of Debrecen, Department of Psychiatry, Faculty of Medicine, Debrecen, Hungary.

MeSH

AnimalsEndoplasmic ReticulumHumansMolecular ChaperonesNeurodegenerative DiseasesReceptors, sigma

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

28554311

Citation

Penke, Botond, et al. "The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases." Current Neuropharmacology, vol. 16, no. 1, 2018, pp. 97-116.
Penke B, Fulop L, Szucs M, et al. The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases. Curr Neuropharmacol. 2018;16(1):97-116.
Penke, B., Fulop, L., Szucs, M., & Frecska, E. (2018). The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases. Current Neuropharmacology, 16(1), 97-116. https://doi.org/10.2174/1570159X15666170529104323
Penke B, et al. The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases. Curr Neuropharmacol. 2018;16(1):97-116. PubMed PMID: 28554311.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases. AU - Penke,Botond, AU - Fulop,Livia, AU - Szucs,Maria, AU - Frecska,Ede, PY - 2016/12/16/received PY - 2017/04/15/revised PY - 2017/05/25/accepted PY - 2017/5/31/pubmed PY - 2018/7/27/medline PY - 2017/5/31/entrez KW - DMT KW - Neurodegenerative diseases KW - agonist KW - antagonist KW - chaperone KW - pharmacology KW - sigma-1 receptor SP - 97 EP - 116 JF - Current neuropharmacology JO - Curr Neuropharmacol VL - 16 IS - 1 N2 - BACKGROUND: Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR). Prolonged chronical UPR may activate apoptotic pathways and cause cell death. METHODS: Research articles on Sigma-1 receptor were reviewed. RESULTS: ER is associated to mitochondria by the mitochondria-associated ER-membrane, MAM. The sigma-1 receptor (Sig-1R), a well-known ER-chaperone localizes in the MAM. It serves for Ca2+-signaling between the ER and mitochondria, involved in ion channel activities and especially important during neuronal differentiation. Sig-1R acts as central modulator in inter-organelle signaling. Sig-1R helps cell survival by attenuating ER-stress. According to sequence based predictions Sig-1R is a 223 amino acid protein with two transmembrane (2TM) domains. The X-ray structure of the Sig-1R [1] showed a membrane-bound trimeric assembly with one transmembrane (1TM) region. Despite the in vitro determined assembly, the results of in vivo studies are rather consistent with the 2TM structure. The receptor has unique and versatile pharmacological profile. Dimethyl tryptamine (DMT) and neuroactive steroids are endogenous ligands that activate Sig-1R. The receptor has a plethora of interacting client proteins. Sig-1R exists in oligomeric structures (dimer-trimer-octamer-multimer) and this fact may explain interaction with diverse proteins. CONCLUSION: Sig-1R agonists have been used in the treatment of different neurodegenerative diseases, e.g. Alzheimer's and Parkinson's diseases (AD and PD) and amyotrophic lateral sclerosis. Utilization of Sig-1R agents early in AD and similar other diseases has remained an overlooked therapeutic opportunity. SN - 1875-6190 UR - https://www.unboundmedicine.com/medline/citation/28554311/The_Role_of_Sigma_1_Receptor_an_Intracellular_Chaperone_in_Neurodegenerative_Diseases_ L2 - https://www.ingentaconnect.com/openurl?genre=article&issn=1570-159X&volume=16&issue=1&spage=97&aulast=Penke DB - PRIME DP - Unbound Medicine ER -