2026-04-13T00:57:51Zhttps://recercat.cat/oai/request
oai:recercat.cat:2072/4696752025-07-29T21:56:42Zcom_2072_98col_2072_378192
RECERCAT author Navarro, Alba author Fernández González, Irene author Riera del Brio, Jordi author Montpeyó Garcia-Moreno, Marta author Albert-Bayo, Mercé author Lopez-Royo, Tresa author Castillo-Sanchez, Pablo author Carnicer-Cáceres, Clara author Arranz-Amo, Jose Antonio author Castillo-Ribelles, Laura author Pradas-Gracia, Eddie author Casas, Josefina author Vila Bover, Miquel author Martinez-Vicente, Marta author Universitat Autònoma de Barcelona 2022 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. open access 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. https://creativecommons.org/licenses/by/4.0/ Cell biology Neurodegeneration Parkinson's disease Pathogenesis Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology Article