Both α-synuclein aggregates in the brain and mutations in the gene GBA1 associate with cognitive decline in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). The goal of this R01 NIH project is to investigate the role of glucosylsphingosine in toxicity caused by pathologic α-syn and mutant GBA1 and explore the potential of inhibiting acid ceramidase as treatment strategy for GBA1-PD conditions. We will accomplish this using mouse models of mutant GBA1 and α-synuclein aggregations along with analysis of glucosylsphingosine in cortex and limbic regions from human PD-GBA1 patients.