Glucocerebrosidase in Parkinson's disease: Insights into pathogenesis and prospects for treatment.

PD involves several converging pathogenetic pathways to neurodegeneration; highlighted in specific cases by genetic mutations causing familial PD. Numerically, the most important genetic mutations associated with PD are those of the glucocerebrosidase gene. Approximately 10% of PD patients carry glucocerebrosidase mutations. This observation has enhanced focus on the autophagy-lysosome system as important in pathogenesis. The relationship of the glucocerebrosidase pathway to the cause and progression of PD highlights the potential to use abnormalities identified as biomarkers and modify glucocerebrosidase activity or substrate accumulation as neuroprotection. Biomarkers relevant to the glucocerebrosidase pathway, for example, enzyme activity and substrate levels, may be identified in blood, urine, and CSF. These may be combined with clinical features to help identify mutation carriers that are at increased risk of PD. The molecular mechanisms by which glucocerebrosidase mutations may result in PD are not fully understood. There is evidence accumulating that there is a reciprocal interaction between glucocerebrosidase and alpha-synuclein levels. This interaction may potentially be used to increase glucocerebrosidase enzyme activities and therefore reduce alpha-synuclein levels to modify the course of PD. Substrate reduction therapy may be an alternative strategy, particularly if membrane abnormalities underlie the organellar dysfunction in PD neurodegeneration.