Objective: The objective of this study was to generate and characterize a new in vitro neuronal model of Parkinson’s diseases associated to GBA (PD-GBA) that allowed us to delve into the elucidation of the link between the loss of GCase and alpha-synuclein (a-syn) pathology.
Background: The first genetic risk factor for developing PD is the presence of mutations in the GBA gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). An inverse relationship between the loss of GCase activity and the accumulation of a-syn has been demonstrated in different PD models, as well as in samples from PD patients carrying GBA mutations. Current available in vitro models present several limitations, thus the development of new neuronal PD-GBA models is crucial to understand the complex molecular mechanisms behind GBA mutations and analyze in detail the contribution of the lysosomal function and lipid metabolism in the pathogenesis of PD.
Method: We have generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations, p.N370S and p.L444P, as well as GBA knock out as an in vitro disease modeling system. We have characterized lysosomal function, including enzyme activity only in lysosomes, macroautophagy, and chaperone-mediated autophagy (CMA). We have characterized the retention of mutant GCase forms in ER, mitochondrial dysfunction, the accumulation of sphingolipids and cholesterol in the lysosomal membrane and the increase of the different neurotoxic species of a-syn.
Results: We described a variety of events triggered by the initial loss of GCase activity leading to intralysosomal accumulation of sphingolipids and cholesterol, lysosomal dysfunction, and impairment of CMA, along with other events previously described in PD-GBA models. These pathogenic mechanisms contribute directly and indirectly to an increase in the accumulation and aggregation of a-syn. Restoration of lysosomal proteolytic capacity and modification of lipid composition can rescue abnormal a-syn accumulation.
Conclusion: Our new in vitro PD-GBA system is a valuable in vitro model that has also allowed us to describe new molecular mechanisms that highlight the role of lysosomal function and lipid metabolism in Parkinson’s disease.
To cite this abstract in AMA style:A. Navarro-Romero, I. Fernandez-Gonzalez, M. Montpeyo, J. Riera, E. Pradas, JA. Arranz, C. Carnicer-Caceres, M. Martinez-Vicente. Lipid metabolism alterations in the lysosomal membrane promotes chaperone-mediated autophagy dysfunction and alpha-synuclein pathology in Parkinson’s disease associated to GBA [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/lipid-metabolism-alterations-in-the-lysosomal-membrane-promotes-chaperone-mediated-autophagy-dysfunction-and-alpha-synuclein-pathology-in-parkinsons-disease-associated-to-gba/. Accessed December 7, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/lipid-metabolism-alterations-in-the-lysosomal-membrane-promotes-chaperone-mediated-autophagy-dysfunction-and-alpha-synuclein-pathology-in-parkinsons-disease-associated-to-gba/