Primary culture of peripheral blood macrophages as a model for screening targeted therapeutics for Parkinson’s disease

Abstract

Parkinson’s disease (PD) associated with mutations in the GBA1 gene (GBA1-PD) represents a promising target for the development of disease-modifying therapies. The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), whose dysfunction leads to the accumulation of its substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Previously, we demonstrated the feasibility of using primary cultures of peripheral blood macrophages as a model for identifying therapeutic targets and compounds aimed at restoring GCase activity. Transcriptomic analysis of these macrophages revealed dysregulation of the PI3K/AKT/mTOR pathway and inflammatory processes in GBA1-PD patients. In this study, we evaluated the potential of mTOR inhibitors, key regulators of autophagy, and STING inhibitors, central mediators of the immune response, as promising therapeutic strategies for reducing GCase substrate accumulation in primary peripheral blood macrophage cultures.