Author(s):
After early skepticism, the association between Gaucher Disease (GD), a rare genetic disease and Parkinson's Disease (PD), the second most common neurodegenerative disorders, is well established, but its underlying mechanisms is controversial: loss of function (haploinsufficiency) or gain of function. Both approaches are supported by apparent suitable animal models. The commentary discusses the failure of substrate reduction therapy and the unlikeliness of success using enzyme replacement therapy (the loss-of-function hypothesis), and predicts future success for pharmacological chaperones, targeting the misfolded mutant glucocerebrosidase for GBA1-related PD (the gain-of-function mechanism). A unique clinical trial (AGPI) is presented, exclusively enrolling GBA1 carriers, focusing on high-dose Ambroxol in early-stage PD for both prevention and disease modification, with the hope to transform the management of GBA1-PD and related disorders.
