Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1G93A ALS Mice

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the death of motoneurons (MNs) with a poor prognosis. There is no available cure, thus, novel therapeutic targets are urgently needed. Sigma-1 receptor (Sig-1R) has been reported as a target to treat experimental models of degenerative diseases and, importantly, mutations in the Sig-1R gene cause several types of motoneuron disease (MND). In this study we compared the potential therapeutic effect of three Sig-1R ligands, the agonists PRE-084 and SA4503 and the antagonist BD1063, in the SOD1G93A mouse model of ALS. Pharmacological administration was from 8 to 16 weeks of age, and the neuromuscular function and disease progression were evaluated using nerve conduction and rotarod tests. At the end of follow up (16 weeks), samples were harvested for histological and molecular analyses. The results showed that PRE-084, as well as BD1063 treatment was able to preserve neuromuscular function of the hindlimbs and increased the number of surviving MNs in the treated female SOD1G93A mice. SA4503 tended to improve motor function and preserved neuromuscular junctions (NMJ), but did not improve MN survival. Western blot analyses revealed that the autophagic flux and the endoplasmic reticulum stress, two pathways implicated in the physiopathology of ALS, were not modified with Sig-1R treatments in SOD1G93A mice. In conclusion, Sig-1R ligands are promising tools for ALS treatment, although more research is needed to ascertain their mechanisms of action.

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Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models

Nature Communications ◽

10.1038/s41467-020-19396-3 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Pin-Tse Lee ◽

Jean-Charles Liévens ◽

Shao-Ming Wang ◽

Jian-Ying Chuang ◽

Bilal Khalil ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Molecular Chaperone ◽

Nucleocytoplasmic Transport ◽

Repeat Expansion ◽

Nuclear Pore ◽

Sigma 1 Receptor ◽

Sigma 1 ◽

Cytoplasmic Accumulation ◽

Nuclear Pore Assembly ◽

Lateral Sclerosis

ABSTRACT In a subgroup of patients with amyotrophic lateral sclerosis (ALS)/Frontotemporal dementia (FTD), the (G4C2)-RNA repeat expansion from C9orf72 chromosome binds to the Ran-activating protein (RanGAP) at the nuclear pore, resulting in nucleocytoplasmic transport deficit and accumulation of Ran in the cytosol. Here, we found that the sigma-1 receptor (Sig-1R), a molecular chaperone, reverses the pathological effects of (G4C2)-RNA repeats in cell lines and in Drosophila. The Sig-1R colocalizes with RanGAP and nuclear pore proteins (Nups) and stabilizes the latter. Interestingly, Sig-1Rs directly bind (G4C2)-RNA repeats. Overexpression of Sig-1Rs rescues, whereas the Sig-1R knockout exacerbates, the (G4C2)-RNA repeats-induced aberrant cytoplasmic accumulation of Ran. In Drosophila, Sig-1R (but not the Sig-1R-E102Q mutant) overexpression reverses eye necrosis, climbing deficit, and firing discharge caused by (G4C2)-RNA repeats. These results on a molecular chaperone at the nuclear pore suggest that Sig-1Rs may benefit patients with C9orf72 ALS/FTD by chaperoning the nuclear pore assembly and sponging away deleterious (G4C2)-RNA repeats.

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Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis

British Journal of Pharmacology ◽

10.1111/bph.15224 ◽

2020 ◽

Cited By ~ 2

Author(s):

Mireia Herrando‐Grabulosa ◽

Núria Gaja‐Capdevila ◽

José M. Vela ◽

Xavier Navarro

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Therapeutic Target ◽

Sigma 1 Receptor ◽

Sigma 1 ◽

Lateral Sclerosis

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A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis

Annals of Neurology ◽

10.1002/ana.22534 ◽

2011 ◽

Vol 70 (6) ◽

pp. 913-919 ◽

Cited By ~ 249

Author(s):

Amr Al-Saif ◽

Futwan Al-Mohanna ◽

Saeed Bohlega

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Sigma 1 Receptor ◽

Juvenile Amyotrophic Lateral Sclerosis ◽

Sigma 1 ◽

Lateral Sclerosis

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γ' Fibrinogen as a Predictor of Survival in Amyotrophic Lateral Sclerosis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.715842 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ana Catarina Pronto-Laborinho ◽

Catarina S. Lopes ◽

Vasco A. Conceição ◽

Marta Gromicho ◽

Nuno C. Santos ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Neurodegenerative Disorder ◽

Positive Impact ◽

Enzyme Linked Immunosorbent Assay ◽

Fibrinogen Concentration ◽

Respiratory Impairment ◽

Increased Risk ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder related to neuroinflammation that is associated with increased risk of thrombosis. We aimed to evaluate γ' fibrinogen plasma level (an in vivo variant of fibrinogen) as a biomarker in ALS, and to test its role as a predictor of disease progression and survival. Sixty-seven consecutive patients with ALS were followed and the results were compared with those from 82 healthy blood donors. Patients were clinically evaluated at the time of blood sampling and on follow-up (every 3 months for the beginning of the follow-up until death) by applying the revised ALS Functional Rating Scale. Human plasma γ' fibrinogen concentration was quantified using a specific two-site sandwich kit enzyme-linked immunosorbent assay. We found, for the first time, a positive association between γ' fibrinogen concentration and survival in ALS patients: patients with higher γ' fibrinogen plasma levels survived longer, and this finding was not influenced by confounders such as age, gender, respiratory impairment, or functionality (ALSFRS-R score). Since increased levels have a positive impact on outcome, this novel biomarker should be further investigated in ALS.

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Stimulation of Sigma-1 Receptor Protects against Cardiac Fibrosis by Alleviating IRE1 Pathway and Autophagy Impairment

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8836818 ◽

2021 ◽

Vol 2021 ◽

pp. 1-25

Author(s):

Jing Qu ◽

Miaoling Li ◽

Dongxu Li ◽

Yanguo Xin ◽

Junli Li ◽

...

Keyword(s):

Cardiac Function ◽

Er Stress ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Cardiac Fibroblast ◽

Autophagic Flux ◽

Sigma 1 Receptor ◽

Fibroblast Activation ◽

Sigma 1 ◽

Stimulation Of

Sigma-1 receptor (Sig1R), a chaperone in the endoplasmic reticulum (ER) membrane, has been implicated in cardiac hypertrophy; however, its role in cardiac fibroblast activation has not been established. This study investigated the possible association between Sig1R and this activation by subjecting mice to sham, transverse aortic constriction (TAC), and TAC plus fluvoxamine (an agonist of Sig1R) treatments. Cardiac function and fibrosis were evaluated four weeks later by echocardiography and histological staining. In an in vitro study, neonatal rat cardiac fibroblasts were treated with fluvoxamine or NE-100 (an antagonist of Sig1R) in the presence or absence of transforming growth factor beta1 (TGF-β1). Fibrotic markers, ER stress pathways, and autophagy were then investigated by qPCR, western blotting, immunofluorescence, confocal microscopy, and transmission electron microscopy. Fluvoxamine treatment reduced cardiac fibrosis, preserved cardiac function, and attenuated cardiac fibroblast activation. Inhibition of the IRE1/XBP1 pathway, a branch of ER stress, by a specific inhibitor of IRE1 endonuclease activity, attenuated the pathological process. Fluvoxamine stimulation of Sig1R restored autophagic flux in cardiac fibroblasts, indicating that Sig1R appears to play a protective role in the activation of cardiac fibroblasts by inhibiting the IRE1 pathway and restoring autophagic flux. Sig1R may therefore represent a therapeutic target for cardiac fibrosis.

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Natural History of “Pure” Primary Lateral Sclerosis

Neurology ◽

10.1212/wnl.0000000000011771 ◽

2021 ◽

Vol 96 (17) ◽

pp. e2231-e2238 ◽

Cited By ~ 1

Author(s):

Anhar Hassan ◽

Shivam Om Mittal ◽

William T. Hu ◽

Keith A. Josephs ◽

Eric J. Sorenson ◽

...

Keyword(s):

Disease Duration ◽

Neurodegenerative Disorder ◽

Retrospective Chart Review ◽

Feeding Tube ◽

Primary Lateral Sclerosis ◽

Bulbar Onset ◽

History Of ◽

Primary Lateral ◽

Lateral Sclerosis

ObjectiveTo assess whether primary lateral sclerosis (PLS), classified as pure when the EMG is normal, converts to amyotrophic lateral sclerosis (ALS) after longitudinal follow-up.MethodsRetrospective chart review was performed of patients with pure PLS at Mayo Clinic in Rochester, MN (1990–2016). Inclusion criteria required a normal EMG during the first 4 years of symptoms.ResultsForty-three patients had pure PLS (25 female, 58%) with a median onset age of 50 years (range 38–78 years) and median follow-up at 9 years’ disease duration (range 4–36 years). The ascending paraparesis phenotype (n = 30, 70%) was most common, followed by hemiparetic onset (n = 9, 21%) and bulbar onset (n = 4, 9%). Among the 30 paraparetic-onset cases, bladder symptoms (n = 18, 60%) and dysarthria (n = 15, 50%) were more common than pseudobulbar affect (n = 9, 30%) and dysphagia (n = 8, 27%). By the last follow-up, 17 of 30 (56%) used a cane and 6 (20%) required a wheelchair. The paraparetic variant, compared with hemiparetic and bulbar onset, had the youngest onset (48 vs 56 vs 60 years, respectively; p = 0.02). Five patients died; 1 patient required a feeding tube; and none required permanent noninvasive ventilation. Two patients developed an idiopathic multisystem neurodegenerative disorder, which surfaced after 19 and 20 years. Two patients developed minor EMG abnormalities. The remainder 39 had persistently normal EMGs.ConclusionsPure PLS did not convert to ALS after a median of 9 years’ disease duration follow-up in our study population. The ascending paraparetic phenotype was most common, with earlier onset and frequent bladder involvement. After years of pure PLS, <5% develop a more pervasive neurodegenerative disorder.

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Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS)

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2014.12.013 ◽

2015 ◽

Vol 127 (1) ◽

pp. 10-16 ◽

Cited By ~ 46

Author(s):

Timur A. Mavlyutov ◽

Lian-Wang Guo ◽

Miles L. Epstein ◽

Arnold E. Ruoho

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Sigma 1 Receptor ◽

Sigma 1 ◽

Lateral Sclerosis

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Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

Cells ◽

10.3390/cells8030211 ◽

2019 ◽

Vol 8 (3) ◽

pp. 211 ◽

Cited By ~ 15

Author(s):

Maximilian Christ ◽

Heike Huesmann ◽

Heike Nagel ◽

Andreas Kern ◽

Christian Behl

Keyword(s):

Clinical Investigation ◽

Receptor Activation ◽

Autophagic Flux ◽

Neuroprotective Effects ◽

Sigma 1 Receptor ◽

C Elegans ◽

Protein Clearance ◽

Sigma 1

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.

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Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis

Human Molecular Genetics ◽

10.1093/hmg/ddz267 ◽

2019 ◽

Cited By ~ 5

Author(s):

Simon Couly ◽

Bilal Khalil ◽

Véronique Viguier ◽

Julien Roussel ◽

Tangui Maurice ◽

...

Keyword(s):

Oxidative Stress ◽

Amyotrophic Lateral Sclerosis ◽

High Energy ◽

Dependent Manner ◽

Wild Type ◽

Sigma 1 Receptor ◽

Atp Levels ◽

Sigma 1 ◽

Lateral Sclerosis

Abstract Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases. However, the pathogenicity of S1RE102Q and the beneficial impact of S1R in the ALS context remain to be demonstrated in vivo. To address this, we generated transgenic Drosophila that express human wild-type S1R or S1RE102Q. Expression of mutant S1R in fly neurons induces abnormal eye morphology and locomotor defects in a dose-dependent manner. This was accompanied by abnormal mitochondrial fragmentation, reduced ATP levels and a higher fatigability at the neuromuscular junction during high energy demand. Overexpressing IP3 receptor or glucose transporter mitigates the S1RE102Q-induced eye phenotype, further highlighting the role of calcium and energy metabolism in its toxicity. More importantly, we showed that wild-type S1R rescues locomotor activity and ATP levels of flies expressing the key ALS protein, TDP43. Moreover, overexpressing wild-type S1R enhances resistance of flies to oxidative stress. Therefore, our data provide the first genetic evidence that mutant S1R recapitulates ALS pathology in vivo while increasing S1R confers neuroprotection against TDP43 toxicity.

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