Insights into GBA Parkinson's disease pathology and therapy with induced pluripotent stem cell model systems.

While the link between GBA and Parkinson's disease (PD) was initially unexpected, it is now well established that GBA mutations are the most frequent genetic risk for PD. GBA has also been linked to sporadic PD, dementia with Lewy bodies, and ageing. Thus, GBA represents a promising target to counteract brain disease and the age-related decline of lysosomal function. The exact mechanisms involved in the risk of developing PD in GBA mutation carriers are still unclear and research in this field has faced the major challenge of a lack of proper modeling systems. Induced pluripotent stem cells (iPSCs) as well as advances in disease modeling and genome editing have facilitated studies of human brain disease. With regard to GBA-PD, iPSCs offer several advantages including the possibility of investigating sphingolipid (SPL) biology in relevant cells, the role of dopamine metabolism as well as non-cell autonomous mechanisms that are likely involved in the disease process. This review will summarize findings that emerged from iPSC-based studies in the context of GBA-PD pathology and therapy. We also highlight current advantages and challenges of stem cell models for neurological disease modeling and drug discovery.