Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB
Summary: Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investiga...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224001809 |
| _version_ | 1797319437074825216 |
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| author | Melania Scarcella Gianluca Scerra Mariangela Ciampa Marianna Caterino Michele Costanzo Laura Rinaldi Antonio Feliciello Serenella Anzilotti Chiara Fiorentino Maurizio Renna Margherita Ruoppolo Luigi Michele Pavone Massimo D’Agostino Valeria De Pasquale |
| author_facet | Melania Scarcella Gianluca Scerra Mariangela Ciampa Marianna Caterino Michele Costanzo Laura Rinaldi Antonio Feliciello Serenella Anzilotti Chiara Fiorentino Maurizio Renna Margherita Ruoppolo Luigi Michele Pavone Massimo D’Agostino Valeria De Pasquale |
| author_sort | Melania Scarcella |
| collection | DOAJ |
| description | Summary: Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs. |
| first_indexed | 2024-03-08T04:06:52Z |
| format | Article |
| id | doaj.art-b7dab594af994d1eb4614b3cad83d1e6 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-08T04:06:52Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-b7dab594af994d1eb4614b3cad83d1e62024-02-09T04:48:54ZengElsevieriScience2589-00422024-03-01273108959Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIBMelania Scarcella0Gianluca Scerra1Mariangela Ciampa2Marianna Caterino3Michele Costanzo4Laura Rinaldi5Antonio Feliciello6Serenella Anzilotti7Chiara Fiorentino8Maurizio Renna9Margherita Ruoppolo10Luigi Michele Pavone11Massimo D’Agostino12Valeria De Pasquale13Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; CEINGE Biotecnologie Avanzate Franco Salvatore, Via G. Salvatore 486, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; CEINGE Biotecnologie Avanzate Franco Salvatore, Via G. Salvatore 486, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, ItalyDepartment of Science and Technology, University of Sannio, Via F. de Sanctis, 82100 Benevento, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; CEINGE Biotecnologie Avanzate Franco Salvatore, Via G. Salvatore 486, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; Corresponding authorDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; Corresponding authorDepartment of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy; Corresponding authorSummary: Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.http://www.sciencedirect.com/science/article/pii/S2589004224001809Human metabolismCell biology |
| spellingShingle | Melania Scarcella Gianluca Scerra Mariangela Ciampa Marianna Caterino Michele Costanzo Laura Rinaldi Antonio Feliciello Serenella Anzilotti Chiara Fiorentino Maurizio Renna Margherita Ruoppolo Luigi Michele Pavone Massimo D’Agostino Valeria De Pasquale Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB iScience Human metabolism Cell biology |
| title | Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB |
| title_full | Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB |
| title_fullStr | Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB |
| title_full_unstemmed | Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB |
| title_short | Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB |
| title_sort | metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis iiib |
| topic | Human metabolism Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224001809 |
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