Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases

Wu, Ning-hua; Ye, Yu; Wan, Bin-bin; Yu, Yuan-Dong; Liu, Chao; Chen, Qingjie

doi:10.1007/s12035-021-02524-5

Cited by 25 publications

(27 citation statements)

References 155 publications

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“…Sig-1R can translocate within the cell to the plasma membrane, where it interacts with ion channels [88]. Pathways by which Sig-1R regulates ER-stress and calcium homeostasis, as well as oxidative stress, have been discovered and validated [89]. According to the latest results, Sig-1R is at the crossroad of proteostasis, neurodegeneration, and autophagy [90]-therefore, a central regulator of cell survival.…”

Section: Molecular Function Of the Sig-1r A Ligand-operated Chaperonementioning

confidence: 99%

“…Sig-1R is highly expressed in the CNS where it possesses very important functions (cell differentiation, formation of axons, synaptic growth, activation of microglia, and regulation of astrocytes) [89]. It regulates neuroprotective mechanisms, e.g., it promotes the expression of BDNF and nerve growth factor (NGF) and also supports neuronal repair.…”

Section: Molecular Function Of the Sig-1r A Ligand-operated Chaperonementioning

confidence: 99%

“…All experimental data so far suggest that activation of Sig-1R improves NDDs by balancing ion homeostasis, regulating ER (and oxidative) stress, promoting the expression of All experimental data so far suggest that activation of Sig-1R improves NDDs by balancing ion homeostasis, regulating ER (and oxidative) stress, promoting the expression of neurotrophic factors, and helping nerve remodeling. Based on these neuroprotective effects, Sig-1R has become one of the most important targets in drug research for the treatment of NDDs [89].…”

Section: Sig-1r As a Central Regulator Of Cell Survival (Er-stress Au...mentioning

confidence: 99%

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Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

2022

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Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other treatments that can stop the progression of NDDs. NDDs have many similarities and common pathways, e.g., formation of misfolded amyloid proteins, intra- and extracellular amyloid deposits, and chronic inflammation. Initially, the inflammation process has a cytoprotective function; however, an elevated and prolonged immune response has damaging effects and causes cell death. Neuroinflammation has been a target of drug development for treating and curing NDDs. Treatment of different NDDs with non-steroid anti-inflammatory drugs (NSAIDs) has failed or has given inconsistent results. The use of NSAIDs in diagnosed Alzheimer’s disease is currently not recommended. Sigma-1 receptor (Sig-1R) is a novel target for NDD drug development. Sig-1R plays a key role in cellular stress signaling, and it regulates endoplasmic reticulum stress and unfolded protein response. Activation of Sig-1R provides neuroprotection in cell cultures and animal studies. Clinical trials demonstrated that several Sig-1R agonists (pridopidine, ANAVEX3-71, fluvoxamine, dextrometorphan) and their combinations have a neuroprotective effect and slow down the progression of distinct NDDs.

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Section: Molecular Function Of the Sig-1r A Ligand-operated Chaperonementioning

confidence: 99%

Section: Molecular Function Of the Sig-1r A Ligand-operated Chaperonementioning

confidence: 99%

Section: Sig-1r As a Central Regulator Of Cell Survival (Er-stress Au...mentioning

confidence: 99%

See 1 more Smart Citation

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

2022

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“…This conservation points towards Sig-1R as a fundamental protein for cell functioning. It is highly expressed in the central nervous system, playing a key role in physiological functions, such as cell differentiation, axon formation, microglial activation, and astrocyte regulation [ 103 ].…”

Section: Therapeutic Approaches Targeting Mamsmentioning

confidence: 99%

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

et al. 2022

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Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

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“…Nguyen, Lucke-Wold, Mookerjee, Kaushal, & Matsumoto, 2017;L. Nguyen et al, 2015;Prause et al, 2013;Smith et al, 2018;Wu et al, 2021). SIGMAR1 has gained considerable attention for its potential to slow the progression of neuron death or reverse an existing pathology of neurodegenerative diseases (Hedskog et al, 2013;Hyrskyluoto et al, 2013;Mori, Hayashi, & Su, 2012;L.…”

Section: Introductionmentioning

confidence: 99%

Generation of Sigmar1 conditional knockout mouse using CRISPR‐Cas9 gene targeting

Huang

Xiao

Xie

et al. 2022

Genesis

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Summary The Sigma 1 receptor (SIGMAR1) is a transmembrane protein located in the mitochondria‐associated endoplasmic reticulum membrane, and plays an important role in cell survival as a pluripotent modulator of a variety of signaling pathways related to neurodegeneration. Though SIGMAR1 is a potential target for neurodegenerative diseases, the specific role of SIGMAR1 in different tissue and cell types remains unclear. Here we reported the generation of Sigmar1 conditional knockout (Sigmar1loxP) mice using CRISPR‐Cas9 method to insert loxP sites into the 5′‐ and 3′‐untranslated regions of Sigmar1. We showed that the insertion of loxP sequences did not affect the expression of Sigmar1 and that Sigmar1loxP/loxP mice exhibited no detectable visual defects compared with wild‐type mice at the early adult stage. By crossing Sigmar1loxP mice with retina‐specific Six3‐Cre and ubiquitous CMV‐Cre mice, we confirmed the deletion of Sigmar1 coding regions of exons 1–4, and the retina‐specific and global loss of SIGMAR1 expression, respectively. Thus, Sigmar1loxP mice provide a valuable tool for unraveling the tissue and cell‐type‐specific role of Sigmar1.

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Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases

Cited by 25 publications

References 155 publications

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Generation of Sigmar1 conditional knockout mouse using CRISPR‐Cas9 gene targeting

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