In summary, GBA mutations likely increase PD risk by the following proposed mechanisms: (1) gain-of-function mechanism where mutant and misfolded GCase accumulates in ER, causing ER stress, (2) loss-of-function mechanism where GCase deficiency causes accumulation of its substrate GlcCer, which stabilizes and promotes α-syn aggregation, and (3) a bi-directional loop where oligomeric α-syn interferes with GCase trafficking, further exacerbating GCase deficiency, leading to more α-syn aggregation. This evidence concerns the gene GBA1 and Parkinson disease.