Role of GlcSph in cognitive deficits in Lewy body dementias - Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB) are two neurodegenerative diseases characterized by cognitive impairments that include executive dysfunction, visual-spatial processing difficulties and impaired working memory. Cognitive impairments are among the most debilitating symptoms of these diseases, often leading to institutionalization and severe decline in health. In PD, cognitive symptoms are often present at diagnosis, but can appear over the course of the disease. In DLB, cognitive changes appear first followed by the development of motor parkinsonism. Both diseases, collectively termed Lewy body dementias, are pathologically characterized by aggregates containing the protein α-synuclein, called Lewy pathology. Lewy pathology is found in brain areas important for cognition including the cortex and hippocampus where it correlates with cognitive decline. Genetic variations in the gene, GBA1, also associate with LBDs. GBA1 encodes for glucocerebrosidase an enzyme that metabolizes glucosylceramide. Mutations in glucocerebrosidase reduce its enzyme activity. Up to 12% of PD cases involved genetic variations in GBA1. The GBA1L444P mutation, which represents about 35% of all PD-GBA1 mutations, increases risk of cognitive decline in PD by 5X. We have found that mice heterozygous for GBA1L444P show impaired performance in behavioral tasks of hippocampal function, and reduced synaptic markers in the hippocampus but not other brain regions. In addition, GBA1L444P heterozygous mice injected with pre-formed α-synuclein fibrils to induce formation of inclusions from endogenous α-synuclein, show more abundant inclusions in the hippocampus compared to wild type mice. In addition, we and others have found that the lipid, glucosylsphingosine but not glucosylceramide is increased in GBA1L444P heterozygous mice, suggesting this lipid causes pathology and should be the target of PD-GBA1 therapies. The combined impact of increased GlcSph and enhanced α-syn aggregation in the hippocampus could be a mechanism by which cognition is impaired in LBDs, which will be explored in this proposal. First, we will determine if glucosylsphingosine is elevated in brain tissue from individuals with PD-GBA1 and controls. We will also utilize a model of human α-synuclein aggregation to determine if pathologic α-synuclein causes changes in glycosphingolipid metabolism in hippocampal and cortical brain regions. Because reduced glucocerebrosidase has been shown to impair lysosome function, we will use primary hippocampal neurons to determine if glucosylsphingosine impairs lysosome activity, leading to a build-up of abnormal α-synuclein. Finally, we will use independent methods to reduce GlcSph in GBA1 L444P heterozygous and wild type mice with and without α-synuclein pathology to determine if decreasing this lipid prevents defects in hippocampal physiology and related behaviors. Overall, this project will help determine mechanisms by which GBA1L444P contributes to cognitive decline and help identify therapeutic strategies to prevent development of cognitive symptoms.
