Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation

Abstract

Mutations inGBA(glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson’s disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred byGBAmutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in aDrosophilamodel of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressingGba1bin activated macrophages suppressed head protein aggregation inGba1bmutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also amelioratedGba1bmutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.Author SummaryMutations in the geneGBAare the largest risk factor for developing Parkinson’s disease and Lewy body dementia, diseases in which important brain cells die. We know that the immune system can be involved in these diseases, and thatGBAmutations cause immune changes. We did experiments to learn how the immune system changes could make brain cells more likely to die. Using a fruit fly that was missing the fly version ofGBA, we found out that inappropriately activated immune cells, but not secreted immune proteins, were important in the development of brain problems. We also learned that the abnormal activation was triggered by the lack ofGBAfunction in the immune cells, not by signals from the brain or other parts of the body. We would like to find out next whether the immune cells get inside the brain or cause harm from a distance. What we learned matters because it could help us prevent or cure brain diseases associated withGBAmutations. Treating the abnormal activation of immune cells in people with these mutations might help prevent damage to the brain.