PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts

Amodio, Giuseppina; Moltedo, Ornella; Fasano, D; Zerillo, Lucrezia; Oliveti, Marco; Pietro, Paola Di; Faraonio, Raffaella; Barone, Paolo; Pellecchia, Maria Teresa; Rosa, Anna De; Michele, Giuseppe De; Polishchuk, Elena; Polishchuk, Roman; Bonifati, Vincenzo; Nitsch, Lucio; Pierantoni, Giovanna Maria; Renna, Maurizio; Criscuolo, Chiara; Paladino, Simona

doi:10.3389/fnins.2019.00673

Cited by 37 publications

(32 citation statements)

References 97 publications

(123 reference statements)

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“…This can cause a cascade of signaling events activating an adaptive pathway to re-establish ER homeostasis, inducing an unfolded protein response (UPR) to mitigate the ER stress condition. Activating transcription factor 6 (ATF6), protein kinase R-like ER kinase (PERK), and inositol-requiring enzyme 1 (IRE1) are the three main transmembrane proteins initiating UPR signaling in ER stress response [5]. In normal conditions they are maintained in an inactive state.…”

Section: Introductionmentioning

confidence: 99%

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

Martucciello

Masullo

Cerulli

et al. 2020

IJMS

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The endoplasmic reticulum (ER) is a dynamic organelle essential for intracellular homeostasis maintenance, controlling synthesis, the folding of secreted and membrane-bound proteins, and transport of Ca2+. During cellular stress, ER dysfunction leads to the activation of unfolded protein response (UPR) due to accumulated misfolded proteins in the ER. This condition is referred as ER stress. Mitochondria and ER form a site of close contact (the mitochondria-associated membrane, MAM) which is a major platform exerting important physiological roles in the regulation of intracellular Ca2+ homeostasis, lipid metabolism, mitochondrial fission, autophagosome formation, and apoptosis progression. Natural products have been receiving increasing attention for their ability to interfere with ER stress. Research works have focused on the capacity of these bioactive compounds to induce apoptosis by activating ER stress through the ER stress-mediated mitochondrial apoptotic pathway. In this review we discuss the role of natural products in the signaling communication between ER and mitochondria, focusing on the effects induced by ER stress including Ca2+ permeability transition and UPR signaling (protein kinase R-like ER kinase/mitofusin 2).

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Section: Introductionmentioning

confidence: 99%

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

Martucciello

Masullo

Cerulli

et al. 2020

IJMS

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“…↑ PERK Human PD brains, rat PD models [231], PARK20 fibroblasts [232], mouse model of chronic MPTP/P injection [233], rat PD model [228], PARK14 mice [224], 6-OHDA-or MPP + -treated MN9D cells [225], Drosophila PINK1 and PARKIN mutants [234], DJ-1 KO MEFs [230]. ↑ eIF2α PARK20 fibroblasts [232], mouse model of chronic MPTP/P injection [233], 6-OHDA-or MPP + -treated MN9D cells [225], DJ-1 KO MEFs [230].…”

Section: Neurodegenerative Disease Upr Markers Experimental Modelmentioning

confidence: 99%

“…Rat PD model [235], PD cellular models [95], mouse model of chronic MPTP/P injection [233], PARK20 fibroblasts [232].…”

Section: ↑ Atf4mentioning

confidence: 99%

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The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

Rozpędek‐Kamińska

Siwecka

Wawrzynkiewicz

et al. 2020

IJMS

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Higher prevalence of neurodegenerative diseases is strictly connected with progressive aging of the world population. Interestingly, a broad range of age-related, neurodegenerative diseases is characterized by a common pathological mechanism—accumulation of misfolded and unfolded proteins within the cells. Under certain circumstances, such protein aggregates may evoke endoplasmic reticulum (ER) stress conditions and subsequent activation of the unfolded protein response (UPR) signaling pathways via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent manner. Under mild to moderate ER stress, UPR has a pro-adaptive role. However, severe or long-termed ER stress conditions directly evoke shift of the UPR toward its pro-apoptotic branch, which is considered to be a possible cause of neurodegeneration. To this day, there is no effective cure for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or prion disease. Currently available treatment approaches for these diseases are only symptomatic and cannot affect the disease progression. Treatment strategies, currently under detailed research, include inhibition of the PERK-dependent UPR signaling branches. The newest data have reported that the use of small-molecule inhibitors of the PERK-mediated signaling branches may contribute to the development of a novel, ground-breaking therapeutic approach for neurodegeneration. In this review, we critically describe all the aspects associated with such targeted therapy against neurodegenerative proteopathies.

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“…A total of 10 µL of each solution, in the presence or absence of 737-786 gp36 CHR-MPER, was taken and spotted onto a cover slip. Images were acquired as previously described [70,71] at 5 and 60 min after deposition on a laser scanning confocal microscope (LSM 510; Carl Zeiss Micro-Imaging) equipped with a plan Apo 63X, NA 1.4 oil immersion objective lens. For each field, both fluorescent and transmitted light images were acquired on separate photomultipliers and were analysed using Zeiss LSM 510 4.0 SP2 software.…”

Section: Confocal Microscope Imagingmentioning

confidence: 99%

NMR Structure of the FIV gp36 C-terminal Heptad Repeat and Membrane-Proximal External Region

Grimaldi

Buonocore

Scrima

et al. 2020

IJMS

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Feline immunodeficiency virus (FIV), a lentivirus causing an immunodeficiency syndrome in cats, represents a relevant model of pre-screening therapies for human immunodeficiency virus (HIV). The envelope glycoproteins gp36 in FIV and gp41 in HIV mediate the fusion of the virus with the host cell membrane. They have a common structural framework in the C-terminal region that includes a Trp-rich membrane-proximal external region (MPER) and a C-terminal heptad repeat (CHR). MPER is essential for the correct positioning of gp36 on the lipid membrane, whereas CHR is essential for the stabilization of the low-energy six-helical bundle (6HB) that is necessary for the fusion of the virus envelope with the cell membrane. Conformational data for gp36 are missing, and several aspects of the MPER structure of different lentiviruses are still debated. In the present work, we report the structural investigation of a gp36 construct that includes the MPER and part of the CHR domain (737-786gp36 CHR–MPER). Using 2D and 3D homo and heteronuclear NMR spectra on 15N and 13C double-labelled samples, we solved the NMR structure in micelles composed of dodecyl phosphocholine (DPC) and sodium dodecyl sulfate (SDS) 90/10 M: M. The structure of 737-786gp36 CHR–MPER is characterized by a helix–turn–helix motif, with a regular α-helix and a moderately flexible 310 helix, characterizing the CHR and the MPER domains, respectively. The two helices are linked by a flexible loop regulating their orientation at a ~43° angle. We investigated the positioning of 737-786gp36 CHR–MPER on the lipid membrane using spin label-enhanced NMR and ESR spectroscopies. On a different scale, using confocal microscopy imaging, we studied the effect of 737-786gp36 CHR–MPER on 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycero-3-phospho-(1’-rac-glycerol) (DOPC/DOPG) multilamellar vesicles (MLVs). This effect results in membrane budding and tubulation that is reminiscent of a membrane-plasticizing role that is typical of MPER domains during the event in which the virus envelope merges with the host cell membrane.

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PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts

Cited by 37 publications

References 97 publications

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

NMR Structure of the FIV gp36 C-terminal Heptad Repeat and Membrane-Proximal External Region

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