Synucleinopathies, including Lewy body dementia (LBD) and Parkinson?s disease (PD), are common and incurable neurodegenerative disorders with strong evidence for heritability. Loss-of-function variants in Glucocerebrosidase (GBA) cause Gaucher?s disease, a recessive lysosomal storage disorder (LSD). It is estimated that 85% or greater loss of Glucocerebrosidase activity is required to trigger Gaucher?s. Paradoxically however, heterozygous carriers of GBA variants?causing modest reductions in overall enzyme function?have a significantly increased risk of PD and LBD, and GBA alleles also dominantly modify risk of dementia among subjects with PD. Emerging evidence suggests that GBA loss of function may enhance the neurotoxicity of ?-synuclein (?Syn), the pathological protein that aggregates to form brain Lewy bodies in PD and LBD. However, the mechanism by which partial reduction in GBA activity contributes to pathogenesis of synucleinopathy remains elusive. Since most GBA variant carriers do not develop disease in their lifetimes, other factors likely contribute to disease penetrance. In an exome-wide study, we discovered an aggregate genetic variant burden among 54 LSD genes associated with PD risk. In fact, over half of subjects carried at least one variant, and 21% carried 2 or more variants. These results suggest that (i) other LSD genes likely contribute to synucleinopathy, and (ii) LSD gene variants may interact with one another to modify risk and progression of neurodegeneration. In this proposal we test the hypothesis that partial, haploinsufficient loss of function in LSD genes disrupts sphingolipid metabolism, leading to enhanced lysosomal stress and increased vulnerability to ?Syn-induced, age-dependent neurodegeneration. In compelling preliminary studies, we have performed comprehensive genetic manipulations of 94 conserved homologs of human LSD genes in a Drosophila transgenic model of ?Syn-mediated neurodegeneration, identifying GBA and 17 other candidate enhancers. A preponderance of modifiers are implicated in lysosomal metabolism of ceramide and sphingolipids. Here, we will employ the powerful and rapid genetics available in Drosophila to systematically confirm interactions between LSD genes and ?Syn-mediated neurodegeneration
Parkinson?s disease and Lewy body dementia are disabling and incurable neurodegenerative disorders affecting more than one million individuals in the US. Integrating recent advances in human genetics with innovative model organism studies, we will elucidate how glucocerebrosidase and related genes implicated in Parkinson?s disease susceptibility disrupt brain metabolism and accelerate disease pathology. Mechanistic dissection of genetic risk factors holds enormous potential for earlier clinical detection and therapeutic breakthroughs.
