beta-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 beta-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson's disease. Despite this evidence, the molecular mechanism linking the impairment in beta-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of beta-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific beta-glucocerebrosidase inhibitor conduritol B epoxide. Neurons deficient for beta-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 beta-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.

β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration / G. Lunghi, E.V. Carsana, N. Loberto, L. Cioccarelli, S. Prioni, L. Mauri, R. Bassi, S. Duga, L. Straniero, R. Asselta, G. Soldà, A. Di Fonzo, E. Frattini, M. Magni, N. Liessi, A. Armirotti, E. Ferrari, M. Samarani, M. Aureli. - In: CELLS. - ISSN 2073-4409. - 11:15(2022 Jul 29), pp. 2343.1-2343.24. [10.3390/cells11152343]

β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration

G. Lunghi
Co-primo
;
E.V. Carsana
Co-primo
;
N. Loberto;S. Prioni;L. Mauri;R. Bassi;S. Duga;L. Straniero;R. Asselta;E. Frattini;E. Ferrari;M. Aureli
Ultimo
2022

Abstract

beta-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 beta-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson's disease. Despite this evidence, the molecular mechanism linking the impairment in beta-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of beta-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific beta-glucocerebrosidase inhibitor conduritol B epoxide. Neurons deficient for beta-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 beta-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.
GBA1; Gaucher disease; glucosylceramide; lipid rafts; lysosomes; plasma membrane; Animals; Cell Membrane; Dopaminergic Neurons; Glucosylceramides; Humans; Lysosomes; Mice; Gaucher Disease; Glucosylceramidase
Settore BIO/10 - Biochimica
   Molecular and cellular mechanism modulating GBA mutation penetrance in Parkinson’s disease
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2017228L3J_002

   Study of the role of the GBA-mediated lysosomal impairment in Parkinson's disease
   FONDAZIONE CARIPLO
   2015-1017
29-lug-2022
29-lug-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/944966
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