Glucocerebrosidase mutations and the pathogenesis of Parkinson disease.

Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease with a lifetime risk in the UK population of almost 5%. An association between PD and Gaucher disease (GD) derived from the observation that GD patients and their heterozygous carrier relatives were at increased risk of PD. GD is an autosomal recessive lysosomal storage disorder caused by homozygous mutations in the gene encoding glucocerebrosidase (GBA). Approximately 5%-10% of PD patients have GBA mutations, making these mutations numerically the most important genetic predisposing risk factor for the development of PD identified to date. GBA mutations result in a phenotype that is virtually indistinguishable clinically, pharmacologically, and pathologically from sporadic PD, except GBA mutations result in a slightly earlier age of onset and more frequent cognitive impairment among PD patients. The mechanisms by which GBA mutations result in PD are not yet understood. Both reduced glucocerebrosidase enzyme (GCase) activity with lysosomal dysfunction, and unfolded protein response (UPR) with endoplasmic reticulum-associated degradation (ERAD) and stress are considered contributory.