Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher's disease (GD), are the strongest genetic risk factor for Parkinson's disease (PD) known to date. Here we generate induced pluripotent stem cells from subjects with GD and PD harbouring GBA1 mutations, and differentiate them into midbrain dopaminergic neurons followed by enrichment using fluorescence-activated cell sorting. Neurons show a reduction in glucocerebrosidase activity and protein levels, increase in glucosylceramide and α-synuclein levels as well as autophagic and lysosomal defects. Quantitative proteomic profiling reveals an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. Mutant neurons show a dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium. Importantly, correction of the mutations rescues such pathological phenotypes. These findings provide evidence for a link between GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration.
Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide 1,2 . Atherosclerotic plaque formation is initiated upon trapping of low-density lipoprotein (LDL) in the subendothelial space of large and medium size arteries that initially involves binding of LDL to heparan-sulfate proteoglycans (HSPGs) 3 , followed by a chronic inflammation and remodelling of the artery wall 3 . A Proliferation Inducing Ligand (APRIL), a cytokine produced by many cell types, binds to HSPGs 4 , but the physiology of this interaction is largely unknown. Here, we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice.Mechanistically, we demonstrate that APRIL confers atheroprotection via binding to heparan sulfate (HS) chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits LDL retention, macrophage accumulation and necrotic core formation. Indeed, antibody-mediated depletion of APRIL in mice expressing HS-deficient HSPG2 had no effect on atherosclerosis development.Consistent with these data, treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduces experimental atherosclerosis. Furthermore, the serum levels of a previously unknown form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long term (10-to 12-year follow up) cardiovascular mortality in patients with atherosclerosis. Our data reveal hitherto unknown properties of APRIL that have broad pathophysiological implications for vascular homeostasis.
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