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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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Autores principales: Lunghi, Giulia, Carsana, Emma Veronica, Loberto, Nicoletta, Cioccarelli, Laura, Prioni, Simona, Mauri, Laura, Bassi, Rosaria, Duga, Stefano, Straniero, Letizia, Asselta, Rosanna, Soldà, Giulia, Di Fonzo, Alessio, Frattini, Emanuele, Magni, Manuela, Liessi, Nara, Armirotti, Andrea, Ferrari, Elena, Samarani, Maura, Aureli, Massimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367513/
https://www.ncbi.nlm.nih.gov/pubmed/35954187
http://dx.doi.org/10.3390/cells11152343
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author Lunghi, Giulia
Carsana, Emma Veronica
Loberto, Nicoletta
Cioccarelli, Laura
Prioni, Simona
Mauri, Laura
Bassi, Rosaria
Duga, Stefano
Straniero, Letizia
Asselta, Rosanna
Soldà, Giulia
Di Fonzo, Alessio
Frattini, Emanuele
Magni, Manuela
Liessi, Nara
Armirotti, Andrea
Ferrari, Elena
Samarani, Maura
Aureli, Massimo
author_facet Lunghi, Giulia
Carsana, Emma Veronica
Loberto, Nicoletta
Cioccarelli, Laura
Prioni, Simona
Mauri, Laura
Bassi, Rosaria
Duga, Stefano
Straniero, Letizia
Asselta, Rosanna
Soldà, Giulia
Di Fonzo, Alessio
Frattini, Emanuele
Magni, Manuela
Liessi, Nara
Armirotti, Andrea
Ferrari, Elena
Samarani, Maura
Aureli, Massimo
author_sort Lunghi, Giulia
collection PubMed
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.
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spelling pubmed-93675132022-08-12 β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration Lunghi, Giulia Carsana, Emma Veronica Loberto, Nicoletta Cioccarelli, Laura Prioni, Simona Mauri, Laura Bassi, Rosaria Duga, Stefano Straniero, Letizia Asselta, Rosanna Soldà, Giulia Di Fonzo, Alessio Frattini, Emanuele Magni, Manuela Liessi, Nara Armirotti, Andrea Ferrari, Elena Samarani, Maura Aureli, Massimo Cells Article 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. MDPI 2022-07-29 /pmc/articles/PMC9367513/ /pubmed/35954187 http://dx.doi.org/10.3390/cells11152343 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lunghi, Giulia
Carsana, Emma Veronica
Loberto, Nicoletta
Cioccarelli, Laura
Prioni, Simona
Mauri, Laura
Bassi, Rosaria
Duga, Stefano
Straniero, Letizia
Asselta, Rosanna
Soldà, Giulia
Di Fonzo, Alessio
Frattini, Emanuele
Magni, Manuela
Liessi, Nara
Armirotti, Andrea
Ferrari, Elena
Samarani, Maura
Aureli, Massimo
β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367513/
https://www.ncbi.nlm.nih.gov/pubmed/35954187
http://dx.doi.org/10.3390/cells11152343
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