β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration
β-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphingolipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk facto...
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MDPI AG
2022-07-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/15/2343 |
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| author | Giulia Lunghi Emma Veronica Carsana Nicoletta Loberto Laura Cioccarelli Simona Prioni Laura Mauri Rosaria Bassi Stefano Duga Letizia Straniero Rosanna Asselta Giulia Soldà Alessio Di Fonzo Emanuele Frattini Manuela Magni Nara Liessi Andrea Armirotti Elena Ferrari Maura Samarani Massimo Aureli |
| author_facet | Giulia Lunghi Emma Veronica Carsana Nicoletta Loberto Laura Cioccarelli Simona Prioni Laura Mauri Rosaria Bassi Stefano Duga Letizia Straniero Rosanna Asselta Giulia Soldà Alessio Di Fonzo Emanuele Frattini Manuela Magni Nara Liessi Andrea Armirotti Elena Ferrari Maura Samarani Massimo Aureli |
| author_sort | Giulia Lunghi |
| collection | DOAJ |
| description | β-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphingolipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson’s disease. Despite this evidence, the molecular mechanism linking the impairment in β-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of β-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific β-glucocerebrosidase inhibitor conduritol B epoxide. Neurons deficient for β-glucocerebrosidase activity showed a lysosomal accumulation of glucosylceramide and the onset of neuronal damage. Moreover, we found that neurons react to the lysosomal impairment by the induction of their biogenesis and exocytosis. This latter event was responsible for glucosylceramide accumulation also at the plasma membrane level, with an alteration in lipid and protein composition of specific signaling microdomains. Collectively, our data suggest that β-glucocerebrosidase loss of function impairs the lysosomal compartment, establishing a lysosome–plasma membrane axis responsible for modifications in the plasma membrane architecture and possible alterations of intracellular signaling pathways, leading to neuronal damage. |
| first_indexed | 2024-03-09T05:30:55Z |
| format | Article |
| id | doaj.art-0c02205b205142f68964b014a1490b02 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T05:30:55Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-0c02205b205142f68964b014a1490b022023-12-03T12:32:14ZengMDPI AGCells2073-44092022-07-011115234310.3390/cells11152343β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of NeurodegenerationGiulia Lunghi0Emma Veronica Carsana1Nicoletta Loberto2Laura Cioccarelli3Simona Prioni4Laura Mauri5Rosaria Bassi6Stefano Duga7Letizia Straniero8Rosanna Asselta9Giulia Soldà10Alessio Di Fonzo11Emanuele Frattini12Manuela Magni13Nara Liessi14Andrea Armirotti15Elena Ferrari16Maura Samarani17Massimo Aureli18Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, ItalyDepartment of Biomedical Sciences, Humanitas University, 20090 Milan, ItalyDepartment of Biomedical Sciences, Humanitas University, 20090 Milan, ItalyDepartment of Biomedical Sciences, Humanitas University, 20090 Milan, ItalyDepartment of Biomedical Sciences, Humanitas University, 20090 Milan, ItalyIRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, ItalyIRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, ItalyIRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, ItalyAnalytical Chemistry Facility, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, ItalyAnalytical Chemistry Facility, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, ItalyDepartment of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, ItalyDepartment of Cell Biology and Infection, Institut Pasteur, 75015 Paris, FranceDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italyβ-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphingolipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson’s disease. Despite this evidence, the molecular mechanism linking the impairment in β-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of β-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific β-glucocerebrosidase inhibitor conduritol B epoxide. Neurons deficient for β-glucocerebrosidase activity showed a lysosomal accumulation of glucosylceramide and the onset of neuronal damage. Moreover, we found that neurons react to the lysosomal impairment by the induction of their biogenesis and exocytosis. This latter event was responsible for glucosylceramide accumulation also at the plasma membrane level, with an alteration in lipid and protein composition of specific signaling microdomains. Collectively, our data suggest that β-glucocerebrosidase loss of function impairs the lysosomal compartment, establishing a lysosome–plasma membrane axis responsible for modifications in the plasma membrane architecture and possible alterations of intracellular signaling pathways, leading to neuronal damage.https://www.mdpi.com/2073-4409/11/15/2343GBA1glucosylceramideGaucher diseaselysosomesplasma membranelipid rafts |
| spellingShingle | Giulia Lunghi Emma Veronica Carsana Nicoletta Loberto Laura Cioccarelli Simona Prioni Laura Mauri Rosaria Bassi Stefano Duga Letizia Straniero Rosanna Asselta Giulia Soldà Alessio Di Fonzo Emanuele Frattini Manuela Magni Nara Liessi Andrea Armirotti Elena Ferrari Maura Samarani Massimo Aureli β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration Cells GBA1 glucosylceramide Gaucher disease lysosomes plasma membrane lipid rafts |
| title | β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration |
| title_full | β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration |
| title_fullStr | β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration |
| title_full_unstemmed | β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration |
| title_short | β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration |
| title_sort | β glucocerebrosidase deficiency activates an aberrant lysosome plasma membrane axis responsible for the onset of neurodegeneration |
| topic | GBA1 glucosylceramide Gaucher disease lysosomes plasma membrane lipid rafts |
| url | https://www.mdpi.com/2073-4409/11/15/2343 |
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