Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
Navarro, Alba (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernández González, Irene (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Riera del Brio, Jordi (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Montpeyó Garcia-Moreno, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Albert-Bayo, Mercé (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Lopez-Royo, Tresa (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Castillo-Sanchez, Pablo (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Carnicer-Cáceres, Clara (Institució Catalana de Recerca i Estudis Avançats)
Arranz-Amo, Jose Antonio (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Castillo-Ribelles, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Pradas-Gracia, Eddie (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Casas, Josefina (Institut de Química Avançada de Catalunya)
Vila Bover, Miquel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martinez-Vicente, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	Mutations in the GBA gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.
Ajuts:	Instituto de Salud Carlos III PI20/00728 Instituto de Salud Carlos III PI17/00496
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cell biology ; Neurodegeneration ; Parkinson's disease ; Pathogenesis
Publicat a:	NPJ Parkinson's disease, Vol. 8 (october 2022) , ISSN 2373-8057

DOI: 10.1038/s41531-022-00397-6
PMID: 36202848

15 p, 2.7 MB

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