Functional impact of an oculopharyngeal muscular dystrophy mutation in PABPN1

García-Castañeda, Maricela; Vega, Alberto; Rodríguez, Rocío Pérez; Montiel-Jaen, María Guadalupe; Cisneros, Bulmaro; Zarain‐Herzberg, Ángel; Ávila, Guillermo

doi:10.1113/jp273948

Cited by 6 publications

(6 citation statements)

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“…Recently, it has been demonstrated that PABPN1 protein regulates nuclear structure and homeostasis of Ca 2+ (67). The ER is an essential intracellular organelle for many cell functions including the maintenance of Ca 2+ homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Calcium is one of the key regulators of cell survival and can induce ER stress-mediated apoptosis (68, 69) mainly through mitochondrial cell death (70). It has been shown that PABPN1 mutation in OPMD gives rise to multiple Ca 2+ defects such as alterations of the sarcoplasmic reticulum (SR) Ca 2+ content, inhibition of the voltage-gated SR calcium release and reduced expression of ryanodine receptor (67). Moreover, the presence of TNNT3 pre-mRNA in nuclear aggregates (42) is associated with aberrant calcium sensitivity in muscle fibres.…”

Section: Discussionmentioning

confidence: 99%

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Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

Malerba

Roth

Harish

et al. 2018

Preprint

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Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease affecting most profoundly eyelid and pharyngeal muscles, leading respectively to ptosis and dysphagia, and proximal limb muscles at later stages. A short abnormal (GCG) triplet expansion in the polyAbinding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. It is commonly accepted that aggregates themselves, the aggregation process and/or the early oligomeric species of PABPN1 are toxic in OPMD. Decreasing PABPN1 aggregate load in animal models of OPMD ameliorates the muscle phenotype. In order to identify a potential therapeutic molecule that would prevent and reduce aggregates, we tested guanabenz acetate (GA), an FDA-approved antihypertensive drug, in OPMD cells as well as in the A17 OPMD mouse model. We demonstrate that treating mice with GA reduces the size and number of nuclear aggregates, improves muscle force, protects myofibres from the pathology-derived turnover and decreases fibrosis. GA is known to target various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress.Here we used a cellular model of OPMD to demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data suggest that modulation of protein folding regulation can be beneficial for OPMD and support the further development of guanabenz or its derivatives for treatment of OPMD in humans. Significance Statement:Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset incurable genetic disease characterized by the formation of insoluble aggregates in skeletal muscles. It has been shown that the reduction of aggregates correlates with an improvement of the disease. Here we used a mouse model of OPMD to show that Guanabenz acetate, the active constituent of a marketed but recently discontinued drug for hypertension, decreases the number and the size of aggregates after systemic delivery and improves many aspects of the disease. We also describe experimental evidences explaining the mechanism behind the efficacy of such compound for OPMD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

Malerba

Roth

Harish

et al. 2018

Preprint

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“…Protein levels of NCX, nNOS and eNOS, were investigated by western-blot analysis (García-Castañeda et al, 2017). The cells were washed with ice-cold PBS and incubated 15 min in lysis buffer (containing inhibitors of proteases and phosphatases).…”

Section: Methodsmentioning

confidence: 99%

Long-Term Regulation of Excitation–Contraction Coupling and Oxidative Stress in Cardiac Myocytes by Pirfenidone

2018

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Pirfenidone (PFD) is used to treat human pulmonary fibrosis. Its administration to animals with distinct forms of cardiovascular disease results in striking improvement in cardiac performance. Here, its functional impact on cardiac myocytes was investigated. Cells were kept 1–2 days under either control culture conditions or the presence of PFD (1 mM). Subsequently, they were subjected to electrical stimulation to assess the levels of contractility and intracellular Ca2+. The PFD treatment promoted an increase in both peak contraction and kinetics of shortening and relaxation. Moreover, the amplitude and kinetics of Ca2+ transients were enhanced as well. Excitation–contraction coupling (ECC) was also investigated, under whole-cell patch-clamp conditions. In keeping with a previous report, PFD increased twofold the density of Ca2+ current (ICa). Notably, a similar increase in the magnitude of Ca2+ transients was also observed. Thus, the gain of ECC was unaltered. Likewise, PFD did not alter the peak amplitude of caffeine-induced Ca2+ release, indicating stimulation of Ca2+-induced–Ca2+-release (CICR) at constant sarcoplasmic reticulum Ca2+ load. A phase-plane analysis indicated that PFD promotes myofilament Ca2+ desensitization, which is being compensated by higher levels of Ca2+ to promote contraction. Interestingly, although the expression of the Na+/Ca2+ exchanger (NCX) was unaffected, the decay of Ca2+ signal in the presence of caffeine was 50% slower in PFD-treated cells (compared with controls), suggesting that PFD downregulates the activity of the exchanger. PFD also inhibited the production of reactive oxygen species, under both, basal conditions and the presence of oxidative insults (acetaldehyde and peroxide hydrogen). Conversely, the production of nitric oxide was either increased (in atrial myocytes) or remained unchanged (in ventricular myocytes). Protein levels of endothelial and neuronal nitric oxide synthases (eNOS and nNOS) were also investigated. eNOS values did not exhibit significant changes. By contrast, a dual regulation was observed for nNOS, which consisted of inhibition and stimulation, in ventricular and atrial myocytes, respectively. In the latter cells, therefore, an up-regulation of nNOS was sufficient to stimulate the synthesis of NO. These findings improve our knowledge of molecular mechanisms of PFD action and may also help in explaining the corresponding cardioprotective effects.

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“…homeostasis of Ca 2+(67). The ER is an essential intracellular organelle for many cell functions including the maintenance of Ca 2+ homeostasis.…”

mentioning

confidence: 99%

“…Calcium is one of the key regulators of cell survival and can induce ER stress-mediated apoptosis(68,69) mainly through mitochondrial cell death(70). It has been shown that PABPN1 mutation in OPMD gives rise to multiple Ca 2+ defects such as alterations of the sarcoplasmic reticulum (SR) Ca 2+ content, inhibition of the voltage-gated SR calcium release and reduced expression of ryanodine receptor(67). Moreover, the presence of TNNT3 pre-mRNA in nuclear aggregates(43) is associated with aberrant calcium sensitivity in muscle fibers.…”

mentioning

confidence: 99%

Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

Malerba

Roth

Harish

et al. 2019

Human Molecular Genetics

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Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease leading to ptosis, dysphagia, and proximal limb muscles at later stages. A short abnormal (GCN) triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. Here we demonstrate that treating mice with guanabenz acetate (GA), an FDA-approved antihypertensive drug, reduces the size and number of nuclear aggregates, improves muscle force, protects myofibers from the pathology-derived turnover and decreases fibrosis. GA targets various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. We demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data show that modulation of protein folding regulation is beneficial for OPMD and promote the further development of GA or its derivatives for treatment of OPMD in humans. Furthermore, they support the recent evidences that treating ER stress could be therapeutically relevant in other more common proteinopathies.

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Functional impact of an oculopharyngeal muscular dystrophy mutation in PABPN1

Cited by 6 publications

References 61 publications

Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

Long-Term Regulation of Excitation–Contraction Coupling and Oxidative Stress in Cardiac Myocytes by Pirfenidone

Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

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