Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy

Montague, Karli; Malik, Bilal; Gray, Anna L.; Spada, Albert R. La; Hanna, Michael G.; Szabadkai, György; Greensmith, Linda

doi:10.1093/brain/awu114

Cited by 32 publications

(31 citation statements)

References 56 publications

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“…As a result, ER stress-mediated apoptosis was activated in AR100 motor neurons in vitro, leading to an increase in the expression of activated caspase 12. Similarly, there was elevation of ER stress markers in vivo, in spinal cord motor neurons of AR100 mice (Montague, et al, 2014). Importantly, this ER stress was detected in presymptomatic mice, long before the onset of any pathology and development of disease, suggesting that ER stress may be an early event in the pathogenesis of SBMA which possibly plays a causal role in the development of the disease.…”

Section: D) Endoplasmic Reticulum-associated Degradation In Stress Comentioning

confidence: 83%

“…The role of ER stress and Ca 2+ homeostasis was recently examined in the AR100 mouse model of SBMA. AR100 mice develop a late onset, slowly progressive neuromuscular phenotype, accompanied by motor neuron degeneration and muscle atrophy (Malik, et al, 2011,Montague, et al, 2014,Sopher, et al, 2004. Dysregulation of Ca 2+ homeostasis in embryonic motor neurons of AR100 mice results in ER stress, which enhances the vulnerability of AR100 motor neurons to ER-stress-induced apoptosis (Montague, et al, 2014).…”

Section: D) Endoplasmic Reticulum-associated Degradation In Stress Comentioning

confidence: 99%

“…AR100 mice develop a late onset, slowly progressive neuromuscular phenotype, accompanied by motor neuron degeneration and muscle atrophy (Malik, et al, 2011,Montague, et al, 2014,Sopher, et al, 2004. Dysregulation of Ca 2+ homeostasis in embryonic motor neurons of AR100 mice results in ER stress, which enhances the vulnerability of AR100 motor neurons to ER-stress-induced apoptosis (Montague, et al, 2014). These findings suggest that in cultured motor neurons of AR100 SBMA mice, ligand-dependant DHT activation of ARpolyQ triggers a depletion of ER Ca 2+ levels and a reduction of store-operated Ca 2+ influx.…”

Section: D) Endoplasmic Reticulum-associated Degradation In Stress Comentioning

confidence: 99%

“…ER stress has been shown to be an early pathological feature of motor neuron disorders, in both the SOD1 G93A mouse model of ALS and the AR100 model of SBMA (Montague, et al, 2014,Saxena, et al, 2009). The effect of pharmacological targeting of ER stress was examined by treatment of AR100 SBMA embryonic motor neuron cultures with the ER inhibitor, salubrinal, in order to establish whether motor neuron survival was related to the ER stress observed in AR100 motor neurons (Montague, et al, 2014).…”

Section: C) Activation Of the Upr Responsementioning

confidence: 99%

“…The effect of pharmacological targeting of ER stress was examined by treatment of AR100 SBMA embryonic motor neuron cultures with the ER inhibitor, salubrinal, in order to establish whether motor neuron survival was related to the ER stress observed in AR100 motor neurons (Montague, et al, 2014). Salubrinal is a selective inhibitor of eIF2α dephosphorylation, and consequently diminishes ER stress-mediated apoptosis (Boyce, et al, 2005,Kessel, 2006.…”

Section: C) Activation Of the Upr Responsementioning

confidence: 99%

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The Role of the Protein Quality Control System in SBMA

et al. 2015

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Spinal and Bulbar Muscular Atrophy (SBMA) or Kennedy's disease is an X-linked disease associated with the expansion of the CAG triplet repeat present in exon-1 on the androgen receptor (AR) gene. This results in the production of a mutant AR containing an elongated polyglutamine tract (polyQ) in its N-terminus. Interestingly, the ARpolyQ becomes toxic only after its activation by the natural androgenic ligands, possibly because of aberrant androgen-induced conformational changes of the ARpolyQ, which generate misfolded species. These misfolded ARpolyQ species must be cleared from motoneurons and muscle cells, and this process is mediated by the protein quality control (PQC) system. Experimental evidence suggested that failure of the PQC pathways occurs in disease, leading to ARpolyQ accumulation and toxicity in the target cells. In these review we summarized the overall impact of mutant and misfolded ARpolyQ on the PQC system and described how molecular chaperons and the degradative pathways (ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and the unfolded protein response (UPR), which activates the endoplasmic reticulum-associated degradation (ERAD)) are differentially affected in SBMA. We also extensively and critically reviewed several molecular and pharmacological approaches proposed to restore a global intracellular activity of the PQC system. Collectively, these data suggest that the fine and delicate equilibrium existing among the different players of the PQC system could be restored in a therapeutic perspective by the synergic/additive activities of compounds designed to tackle sequential or alternative steps of the intracellular defense mechanisms triggered against proteotoxic misfolded species.

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Section: D) Endoplasmic Reticulum-associated Degradation In Stress Comentioning

confidence: 83%

Section: D) Endoplasmic Reticulum-associated Degradation In Stress Comentioning

confidence: 99%

Section: D) Endoplasmic Reticulum-associated Degradation In Stress Comentioning

confidence: 99%

Section: C) Activation Of the Upr Responsementioning

confidence: 99%

Section: C) Activation Of the Upr Responsementioning

confidence: 99%

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The Role of the Protein Quality Control System in SBMA

et al. 2015

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Effects of calpain inhibitor on the apoptosis of hepatic stellate cells induced by calcium ionophore A23187

Liu

et al. 2018

J of Cellular Biochemistry

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We previously showed that changes in calcium concentrations were related to cell apoptosis in vitro. The endoplasmic reticulum (ER) is the main component of calcium storage and signal transduction, and disrupting the balance of intracellular Ca can cause endoplasmic reticulum stress (ERS). In this process, the ER releases stored Ca into the cytoplasm and activates calpain-2. To further investigate the effect of calpain in hepatic stellate cells (HSCs), in the current study, we examine the effect of N-acetyl-leu-leu-norleucinal (ALLN) on apoptosis resulting from calcium ionophore A23187-induced ERS. Our findings indicate that calpain inhibition reduces calcium ionophore A23187-induced apoptosis of HSCs and decreases the expression of ER stress proteins that may be related to the calpain/caspase signaling pathway.

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Endoplasmic reticulum stress promotes sepsis‐induced muscle atrophy via activation of STAT3 and Smad3

Zheng

Dai

Chen

et al. 2023

Journal Cellular Physiology

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Endoplasmic reticulum (ER) stress is involved in skeletal muscle atrophy in various conditions, but the role of ER stress in sepsis‐induced muscle atrophy is not well understood. In this study, we conducted experiments in wild‐type (WT) mice and C/EBP homologous protein knockout (CHOP KO) mice to explore the role and mechanism of ER stress in sepsis‐induced muscle atrophy. Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis. In WT mice, the body weight, muscle mass, and cross‐sectional area of muscle fibers in CLP group both decreased significantly compared with sham group, which revealed that sepsis‐induced dramatic muscle atrophy. Additionally, sepsis activated the ubiquitin‐proteasome system (UPS), accompanied by the activation of ER stress. In vitro, inhibition of ER stress suppressed the activity of E3 ubiquitin ligases and alleviated the myotube atrophy. In vivo, CHOP KO also reduced the expression of E3 ubiquitin ligases and UPS‐mediated protein degradation, and significantly attenuated sepsis‐induced muscle atrophy. Deletion of CHOP also decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and Smad3, and inhibition of STAT3 and Smad3 partly reduced proteolysis caused by ER stress in vitro. These findings confirm that ER stress activates UPS‐mediated proteolysis and promotes sepsis‐induced muscle atrophy, which is partly achieved by activating STAT3 and Smad3.

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Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy

Cited by 32 publications

References 56 publications

The Role of the Protein Quality Control System in SBMA

The Role of the Protein Quality Control System in SBMA

Effects of calpain inhibitor on the apoptosis of hepatic stellate cells induced by calcium ionophore A23187

Endoplasmic reticulum stress promotes sepsis‐induced muscle atrophy via activation of STAT3 and Smad3

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