Instituto de Medicina Molecular, Portugal
Stalled lysosomes prime cell proliferation
Lysosomes play a critical role in autophagy, and their dysfunction is associated with Parkinson’s disease (PD). Heterozygous mutations in the GBA1 gene, which encodes for the lysosomal enzyme b-glucocerebrosidase (Gcase), are a risk factor for PD. To investigate the effect of GCase loss-offunction on cellular metabolism, we exposed cultured cells to CBE, which is a specific inhibitor of GCase. Transcriptomic analysis of human primary fibroblasts treated with CBE revealed an upregulation of genes involved in cell division. Consistent with this result, CBE increased the proportion of cells in S phase and the total number of cells in the cultures. We further observed that CBE stimulated the proliferation of neural stem cells isolated from the subventricular zone of new born mouse brains. Neural stem cells were cultured as neurospheres for 7 days with or without 5µM CBE. Compared to mock-treated cultures, the cultures treated with CBE showed a higher proportion of cells in S-phase, and an increase in the total number of cells. An increase in the diameter of neurospheres was also observed. Taken together our results suggest that inhibition of bglucocerebrosidase activity leads to increased cell proliferation. These observations raise the possibility that loss-of-function mutations in the GBA1 gene may interfere with the cell-cycle control of neural stem cells in the human brain.