PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts
PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-06-01
|
| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00673/full |
| _version_ | 1811283692341952512 |
|---|---|
| author | Giuseppina Amodio Ornella Moltedo Dominga Fasano Lucrezia Zerillo Marco Oliveti Paola Di Pietro Raffaella Faraonio Paolo Barone Maria Teresa Pellecchia Anna De Rosa Giuseppe De Michele Elena Polishchuk Roman Polishchuk Vincenzo Bonifati Lucio Nitsch Giovanna Maria Pierantoni Maurizio Renna Chiara Criscuolo Simona Paladino Paolo Remondelli |
| author_facet | Giuseppina Amodio Ornella Moltedo Dominga Fasano Lucrezia Zerillo Marco Oliveti Paola Di Pietro Raffaella Faraonio Paolo Barone Maria Teresa Pellecchia Anna De Rosa Giuseppe De Michele Elena Polishchuk Roman Polishchuk Vincenzo Bonifati Lucio Nitsch Giovanna Maria Pierantoni Maurizio Renna Chiara Criscuolo Simona Paladino Paolo Remondelli |
| author_sort | Giuseppina Amodio |
| collection | DOAJ |
| description | PARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2α/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease. |
| first_indexed | 2024-04-13T02:17:16Z |
| format | Article |
| id | doaj.art-b26864833e714333b88e97b9181fbe9e |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-13T02:17:16Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-b26864833e714333b88e97b9181fbe9e2022-12-22T03:07:07ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-06-011310.3389/fnins.2019.00673461384PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 FibroblastsGiuseppina Amodio0Ornella Moltedo1Dominga Fasano2Lucrezia Zerillo3Marco Oliveti4Paola Di Pietro5Raffaella Faraonio6Paolo Barone7Maria Teresa Pellecchia8Anna De Rosa9Giuseppe De Michele10Elena Polishchuk11Roman Polishchuk12Vincenzo Bonifati13Lucio Nitsch14Giovanna Maria Pierantoni15Maurizio Renna16Chiara Criscuolo17Simona Paladino18Paolo Remondelli19Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, ItalyDepartment of Pharmacy, University of Salerno, Salerno, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, ItalyDepartment of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalySection of Neuroscience, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, ItalySection of Neuroscience, Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, ItalyDepartment of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples, ItalyDepartment of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples, ItalyTelethon Institute of Genetics and Medicine, Pozzuoli, ItalyTelethon Institute of Genetics and Medicine, Pozzuoli, ItalyDepartment of Clinical Genetics, Erasmus MC, Rotterdam, NetherlandsDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, ItalyDepartment of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, ItalyPARK20, an early onset autosomal recessive parkinsonism is due to mutations in the phosphatidylinositol-phosphatase Synaptojanin 1 (Synj1). We have recently shown that the early endosomal compartments are profoundly altered in PARK20 fibroblasts as well as the endosomal trafficking. Here, we report that PARK20 fibroblasts also display a drastic alteration of the architecture and function of the early secretory compartments. Our results show that the exit machinery from the Endoplasmic Reticulum (ER) and the ER-to-Golgi trafficking are markedly compromised in patient cells. As a consequence, PARK20 fibroblasts accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress. Interestingly, this stressful state is coupled to the activation of the PERK/eIF2α/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). In addition, PARK20 fibroblasts reveal upregulation of oxidative stress markers and total ROS production with concomitant alteration of the morphology of the mitochondrial network. Interestingly, treatment of PARK20 cells with GSK2606414 (GSK), a specific inhibitor of PERK activity, restores the level of ROS, signaling a direct correlation between ER stress and the induction of oxidative stress in the PARK20 cells. All together, these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease.https://www.frontiersin.org/article/10.3389/fnins.2019.00673/fullPARK20PERK (PKR-like endoplasmic reticulum kinase)oxydative stressER stressSynaptojanin 1membrane trafficking |
| spellingShingle | Giuseppina Amodio Ornella Moltedo Dominga Fasano Lucrezia Zerillo Marco Oliveti Paola Di Pietro Raffaella Faraonio Paolo Barone Maria Teresa Pellecchia Anna De Rosa Giuseppe De Michele Elena Polishchuk Roman Polishchuk Vincenzo Bonifati Lucio Nitsch Giovanna Maria Pierantoni Maurizio Renna Chiara Criscuolo Simona Paladino Paolo Remondelli PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts Frontiers in Neuroscience PARK20 PERK (PKR-like endoplasmic reticulum kinase) oxydative stress ER stress Synaptojanin 1 membrane trafficking |
| title | PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts |
| title_full | PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts |
| title_fullStr | PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts |
| title_full_unstemmed | PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts |
| title_short | PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts |
| title_sort | perk mediated unfolded protein response activation and oxidative stress in park20 fibroblasts |
| topic | PARK20 PERK (PKR-like endoplasmic reticulum kinase) oxydative stress ER stress Synaptojanin 1 membrane trafficking |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00673/full |
| work_keys_str_mv | AT giuseppinaamodio perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT ornellamoltedo perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT domingafasano perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT lucreziazerillo perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT marcooliveti perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT paoladipietro perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT raffaellafaraonio perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT paolobarone perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT mariateresapellecchia perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT annaderosa perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT giuseppedemichele perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT elenapolishchuk perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT romanpolishchuk perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT vincenzobonifati perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT lucionitsch perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT giovannamariapierantoni perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT mauriziorenna perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT chiaracriscuolo perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT simonapaladino perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts AT paoloremondelli perkmediatedunfoldedproteinresponseactivationandoxidativestressinpark20fibroblasts |