Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases

McLaughlin, Todd; Falkowski, Marek; Wang, Joshua J.; Zhang, Sarah X.

doi:10.1007/978-3-319-75402-4_52

Cited by 22 publications

(15 citation statements)

References 22 publications

(32 reference statements)

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“…In accordance, the protein TXN is responsible for mitochondrial redox homeostasis and acts as important regulator of the energy metabolism in neuronal cells [72]. On the contrary, the proteins HSP90AA1, HSPE1 and ERP29 are mainly functional as molecular chaperone complexes essential for the maintenance of the protein folding and protein trafficking, (see Table 2 and File S3) during cellular stress responses and are a hallmark for various neurodegenerative diseases, including glaucoma [73,74,75]. Mitochondrial dysfunction, the protein ubiquitination pathway and oxidative phosphorylation (Table 1) were annotated as the three main affected canonical pathways and are recognized as the primarily responsible pathological factors in glaucoma [76,77,78,79].…”

Section: Discussionmentioning

confidence: 99%

Synthetic Polyclonal-Derived CDR Peptides as an Innovative Strategy in Glaucoma Therapy

Schmelter

Fomo

Perumal

et al. 2019

JCM

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The pathogenesis of glaucoma is strongly associated with the occurrence of autoimmune-mediated loss of retinal ganglion cells (RGCs) and additionally, recent evidence shows that specific antibody-derived signature peptides are significantly differentially expressed in sera of primary-open angle glaucoma patients (POAG) compared to healthy controls. Synthetically antibody-derived peptides can modulate various effector functions of the immune system and act as antimicrobial or antiviral molecules. In an ex vivo adolescent glaucoma model, this study, for the first time, demonstrates that polyclonal-derived complementarity-determining regions (CDRs) can significantly increase the survival rate of RGCs (p = 0.013). We subsequently performed affinity capture experiments that verified the mitochondrial serine protease HTRA2 (gene name: HTRA2) as a high-affinity retinal epitope target of CDR1 sequence motif ASGYTFTNYGLSWVR. Quantitative proteomic analysis of the CDR-treated retinal explants revealed increased expression of various anti-apoptotic and anti-oxidative proteins (e.g., VDAC2 and TXN) compared to untreated controls (p < 0.05) as well as decreased expression levels of cellular stress response markers (e.g., HSPE1 and HSP90AA1). Mitochondrial dysfunction, the protein ubiquitination pathway and oxidative phosphorylation were annotated as the most significantly affected signaling pathways and possibly can be traced back to the CDR-induced inhibition or modulation of the master regulator HTRA2. These findings emphasize the great potential of synthetic polyclonal-derived CDR peptides as therapeutic agents in future glaucoma therapy and provide an excellent basis for affinity-based biomarker discovery purposes.

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Section: Discussionmentioning

confidence: 99%

Synthetic Polyclonal-Derived CDR Peptides as an Innovative Strategy in Glaucoma Therapy

Schmelter

Fomo

Perumal

et al. 2019

JCM

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“…Hspa8 is also involved in mitochondrial protein import and β-amyloid (Aβ) clearance in the brain [61]. Erp29 is an endoplasmic reticulum (ER) luminal protein acting as a molecular chaperon in ER homeostasis, protein folding and trafficking, and cell survival [62]. A recent study indicated that Erp29 exerts neuroprotective effects through protecting neurons from apoptosis and promoting neuronal regeneration [63].…”

Section: Discussionmentioning

confidence: 99%

γ-Oryzanol Improves Cognitive Function and Modulates Hippocampal Proteome in Mice

et al. 2019

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Rice (Oryza sativa L.) is the richest source of γ-oryzanol, a compound endowed with antioxidant and anti-inflammatory properties. γ-Oryzanol has been demonstrated to cross the blood-brain barrier in intact form and exert beneficial effects on brain function. This study aimed to clarify the effects of γ-oryzanol in the hippocampus in terms of cognitive function and protein expression. Adult mice were administered with γ-oryzanol 100 mg/kg or vehicle (control) once a day for 21 consecutive days following which cognitive behavior and hippocampal proteome were investigated. Cognitive tests using novel object recognition and Y-maze showed that long-term consumption of γ-oryzanol improves cognitive function in mice. To investigate the hippocampal proteome modulated by γ-oryzanol, 2D-difference gel electrophoresis (2D-DIGE) was performed. Interestingly, we found that γ-oryzanol modulates quantitative changes of proteins involved in synaptic plasticity and neuronal trafficking, neuroprotection and antioxidant activity, and mitochondria and energy metabolism. These findings suggested γ-oryzanol as a natural compound able to maintain and reinforce brain function. Although more intensive studies are needed, we propose γ-oryzanol as a putative dietary phytochemical for preserving brain reserve, the ability to tolerate age-related changes, thereby preventing clinical symptoms or signs of neurodegenerative diseases.

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“…While our GRP78 test verified that L-Z reduced the ERS, we are also interested in the expression of endoplasmic reticulum protein 29 (ERp29) which was investigated in recent retinal studies [67, 68]. ERp29, ubiquitously expressed in the ER membrane among various tissues and cell types, is an ER luminal protein in all mammals [69, 70].…”

Section: Discussionmentioning

confidence: 94%

“…ERp29, ubiquitously expressed in the ER membrane among various tissues and cell types, is an ER luminal protein in all mammals [69, 70]. It plays a pivotal role in modulating the folding and transportation of proteins during ERS [67]. GRP78 is one of the main targets of ERp29 [69].…”

Section: Discussionmentioning

confidence: 99%

Lutein and Zeaxanthin Isomers Reduce Photoreceptor Degeneration in the Pde6b^rd10 Mouse Model of Retinitis Pigmentosa

Yan

Beight

2018

BioMed Research International

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Purpose Lutein, RR-zeaxanthin, and RS-zeaxanthin (L-Z) are antioxidants which can reduce endoplasmic reticulum stress (ERS) and oxidative stress (OS), and ameliorate neurodegenerative diseases. However, their treatment effect in the Pde6brd10 (rd10) mouse model of retinitis pigmentosa (RP) and the underlying cellular mechanisms have not been studied. ERS is an important factor which causes photoreceptor apoptosis. The aim of the current project is to test the treatment effect of L-Z in rd10 mice and to investigate the underlying molecular mechanisms of ERS. Methods L-Z (Lutemax 2020, 10 mg/kg) diluted in sunflower oil (SFO, 1 mg/ml) or the same volume of SFO was administrated via gavage from postnatal day 6 (P6) to P20 daily in L-Z group (n=5) or SFO group (n=6) of rd10 mice. At P21, electroretinography (ERG) was performed to show the functional change of retinas. 78 kDa glucose-regulated protein (GRP78) and endoplasmic reticulum protein 29 (ERp29) were tested by western blot and immunostaining. Results The ERG amplitudes were larger in the L-Z group than those of the SFO group in all flash luminances of dark-adapted and light-adapted ERG (all p < 0.01). Western blot revealed that GRP78 in the retinas of the L-Z group was significantly downregulated compared to that of the SFO group (p < 0.01). Meanwhile, the retinal ERp29 protein was significantly upregulated in the L-Z treatment group than that of the SFO group (p < 0.01). Conclusions L-Z provide protection to the photoreceptors of rd10 mouse model of RP, which is probably associated with the reduction of ERS.

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Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases

Cited by 22 publications

References 22 publications

Synthetic Polyclonal-Derived CDR Peptides as an Innovative Strategy in Glaucoma Therapy

Synthetic Polyclonal-Derived CDR Peptides as an Innovative Strategy in Glaucoma Therapy

γ-Oryzanol Improves Cognitive Function and Modulates Hippocampal Proteome in Mice

Lutein and Zeaxanthin Isomers Reduce Photoreceptor Degeneration in the Pde6b^rd10 Mouse Model of Retinitis Pigmentosa

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Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases

Cited by 22 publications

References 22 publications

Synthetic Polyclonal-Derived CDR Peptides as an Innovative Strategy in Glaucoma Therapy

Synthetic Polyclonal-Derived CDR Peptides as an Innovative Strategy in Glaucoma Therapy

γ-Oryzanol Improves Cognitive Function and Modulates Hippocampal Proteome in Mice

Lutein and Zeaxanthin Isomers Reduce Photoreceptor Degeneration in the Pde6brd10 Mouse Model of Retinitis Pigmentosa

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Product

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Lutein and Zeaxanthin Isomers Reduce Photoreceptor Degeneration in the Pde6b^rd10 Mouse Model of Retinitis Pigmentosa