Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB
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
Affiliations
Melania Scarcella
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Gianluca Scerra
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Mariangela Ciampa
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Marianna Caterino
Department 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, Italy
Michele Costanzo
Department 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, Italy
Laura Rinaldi
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Antonio Feliciello
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Serenella Anzilotti
Department of Science and Technology, University of Sannio, Via F. de Sanctis, 82100 Benevento, Italy
Chiara Fiorentino
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Maurizio Renna
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
Margherita Ruoppolo
Department 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, Italy
Luigi Michele Pavone
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; Corresponding author
Massimo D’Agostino
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; Corresponding author
Valeria De Pasquale
Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via F. Delpino 1, 80137 Naples, Italy; Corresponding author
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.
