Sigma 1 receptor activation modifies intracellular calcium exchange in the G93AhSOD1 ALS model

Tadić, Vedrana; Malci, Ayse; Goldhammer, Nadine; Stubendorff, Beatrice; Sengupta, Saikata; Prell, Tino; Keiner, Silke; Liu, Jingyu; Guenther, Madlen; Frahm, Christiane; Witte, Otto W.; Großkreutz, Julian

doi:10.1016/j.neuroscience.2017.07.012

Cited by 22 publications

(17 citation statements)

References 57 publications

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“…Indeed, different ligands may provoke various effects, even acting opposite in the regulation of calcium homeostasis and neuronal excitability. A recent work reported that intracellular calcium shuttling can be manipulated by Sig-1R activation; the SA4503 ligand accelerated cytosolic calcium clearance after AMPA receptor activation and IP3R-mediated ER calcium release, whereas PRE-084 did not exert any significant effect on cytosolic calcium levels in SOD1 G93A mice cultured MNs [46]. Thus, we found promising results with different types of compounds that have high affinity to Sig-1R.…”

Section: Discussionmentioning

confidence: 60%

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Gaja-Capdevila

Hernández

Zamanillo³

et al. 2021

IJMS

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Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries.

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Section: Discussionmentioning

confidence: 60%

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Gaja-Capdevila

Hernández

Zamanillo³

et al. 2021

IJMS

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“…In 2017, the efficacy of another Sig-1R agonist, SA4503, on cultured embryonic mice spinal neurons carrying an ALS-causing mutation was demonstrated. Sig-1R can manipulate Ca 2+ signaling, preventing cytosolic accumulation of this second messenger (Tadic et al, 2017). Available from: https://www.ncbi.nlm.nih.gov/books/NBK1358/).…”

Section: Mams In Diseases Neurodegenerative Diseasesmentioning

confidence: 99%

The role of mitochondria-associated membranes in cellular homeostasis and diseases

Perrone

Caroccia

Genovese

et al. 2020

Biology of the Endoplasmic Reticulum

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Mitochondria and endoplasmic reticulum (ER) are fundamental in the control of cell physiology regulating several signal transduction pathways. They continuously communicate exchanging messages in their contact sites called MAMs (Mitochondria-Associated Membranes). MAMs are specific microdomains acting as a platform for the sorting of vital and dangerous signals.In recent years increasing evidence reported that multiple scaffold proteins and regulatory factors localize to this subcellular fraction suggesting MAMs as hotspot signaling domains. In this review we describe the current knowledge about MAMs' dynamics and processes, which provided new correlations between MAMs' dysfunctions and human diseases. Infact, MAMs machinery is strictly connected with several pathologies, like neurodegeneration, diabetes and mainly cancer. These pathological events are characterized by alterations in the normal communication between ER and mitochondria, leading to deep metabolic defects that contribute to the progression of the diseases.MFN2 defining it as a ER-mitochondria tether whose ablation decreases interorganellar juxtaposition and communication (Naon et al., 2016). This topic is still controversial with opposite results (Filadi et al., 2017) which allow for further considerations about MFN2 functions. Another protein complex whose function is to modulate ER-mitochondria juxtaposition is the complex formed by inositol 1,4,5-trisphosphate receptors (IP3Rs), the voltage-dependent anion channel (VDAC) and the OMM chaperone Grp75 as described in Figure 1 (Szabadkai et al., 2006). This interaction is considered functional because it promotes the efficient transfer of calcium from the ER to mitochondria. In fact, silencing of Grp75 in HeLa cells abolished Ca 2+ accumulation in mitochondria, highlighting chaperone-mediated conformational coupling between the IP3R and mitochondrial machinery. Nevertheless, a recent study of Bartok et al. reveals a non-canonical and structural role for the IP3Rs independently from calcium flux (Bartok et al., 2019).They display that IP3Rs are required for maintaining ER-mitochondrial contacts. Recently, a study of the Transglutaminase type 2 (TG2) interactome showed an enzymatic interaction with GRP75 in the MAM fraction (D'Eletto et al., 2018). In fact, silencing of the TG2-GRP75 complex leads to an increase in the interaction between IP3R-3 and GRP75, a reduction in the number of ER-mitochondria contact sites, impairment of ER-mitochondrial Ca 2+ flux and an altered MAM proteome profile. Furthermore, the complex formed between ER vesicle-associated membrane protein-associated protein B (VAPB) and PTPIP51 regulates the modulation of Ca 2+ homeostasis by MAMs (De Vos et al., 2012).

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“…Nevertheless, different sigma 1 receptor ligands may act differently and even contrarily, on these protective mechanisms. A recent work reported that the SA4503 ligand enhances the cytosolic Ca 2+ clearance after AMPA receptor activation and IP 3 R‐mediated ER Ca 2+ release in motoneurons, whereas the agonist PRE‐084 did not modify the cytosolic calcium levels (Tadić et al, 2017). These observations suggest that different sigma 1 receptor ligands may act differently on the mitochondria‐associated ER membrane regulated calcium homeostasis.…”

Section: Therapeutic Perspectives Targeting Sigma 1 Receptor In Motonmentioning

confidence: 99%

“…Mitochondria-associated-ER membrane alterations have been found in ALS cell models linked to vesicle-associated membrane proteinassociated protein B (De Vos et al, 2012), TDP-43 (Stoica et al, 2014) and fused in sarcoma (Stoica et al, 2016), indicating that dysfunction of the mitochondria-associated ER membrane seems involved in motoneuron degeneration due to different causes.…”

Section: Sigma 1 Receptor Modulates Mitochondriaassociated-er Membrmentioning

confidence: 99%

Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis

Herrando-Grabulosa

Gaja-Capdevila

Vela

et al. 2020

British J Pharmacology

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Amyotrophic lateral sclerosis (ALS) is an adult disease causing a progressive loss of upper and lower motoneurons, muscle paralysis and early death. ALS has a poor prognosis of 3–5 years after diagnosis with no effective cure. The aetiopathogenic mechanisms involved include glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial alterations, disrupted axonal transport and inflammation. Sigma non‐opioid intracellular receptor 1 (sigma 1 receptor) is a protein expressed in motoneurons, mainly found in the endoplasmic reticulum (ER) on the mitochondria‐associated ER membrane (MAM) or in close contact with cholinergic postsynaptic sites. MAMs are sites that allow the assembly of several complexes implicated in essential survival cell functions. The sigma 1 receptor modulates essential mechanisms for motoneuron survival including excitotoxicity, calcium homeostasis, ER stress and mitochondrial dysfunction. This review updates sigma 1 receptor mechanisms and its alterations in ALS, focusing on MAM modulation, which may constitute a novel target for therapeutic strategies. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc

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Sigma 1 receptor activation modifies intracellular calcium exchange in the G93AhSOD1 ALS model

Cited by 22 publications

References 57 publications

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

The role of mitochondria-associated membranes in cellular homeostasis and diseases

Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis

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