Massimo Aureli

Università degli Studi di Milano, Italy

Lysosomal Storage Diseases: involvement of the plasma membrane in the onset of cell damage

Lysosomal Storage Diseases are severe inherited metabolic disorders caused by loss of function mutations in specific lysosomal hydrolases with the consequent accumulation of uncatabolized substrates. Elucidating the molecular mechanism connecting lysosomal impairment with the onset of cell damage occurring in these pathologies remains one of the most important challenges in the field. In my talk I would like to discuss the new insight that we obtained at this regard. In particular, using a simple but reliable in-vitro model of lysosomal storage disorders represented by human fibroblasts loaded with sucrose, we described the existence of a lysosome-plasma membrane axis responsible for the onset of cell damage upon the aberrant accumulation of uncatabolized material in the lysosomes. In addition, recent data elucidated the role of β-glucocerebrosidase deficiency in the onset of cell damage, typical feature of Gaucher and GBA-related Parkinsons’ disease. We developed an in-vitro model of the neuronal form of GD represented by both primary murine granule cells and human iPSCs-derived dopaminergic neurons treated with Conduritol B Epoxide (CBE), a specific inhibitor of GCase. CBE-treated neurons showed the accumulation of GlcCer and the onset of neurodegeneration. Interestingly, using these experimental models, we observed that GlcCer accumulation is not confined to the lysosomes but occurs also at PM level and in the vesicles released in the extracellular milieu. In conclusion, our data together with some other evidences reported in literature highlight the capability of impaired lysosomes in modifying the plasma membrane structure that is responsible, at least in part, for the onset of cell damage.

©2020 by Sphingolipid Biology: Sphingolipids in Physiology and Pathology