GBA2 lipidomics

From Pathophysiology to Therapeutic Targets: Disturbed Sphingolipid Matabolism in HSP Caused by GBA2 Mutations

01/02/2019 to 31/03/2021

Mutations in the GBA2 gene encoding non-lysosomal β-glucosidase cause autosomal- recessive Hereditary Spastic Paraplegia type SPG46. While non-lysosomal β-glucosidase is known to break down glucosylceramide into glucose and ceramide in vitro, its biological function is unknown. We have used CRISPR/Cas9 genome editing to correct the GBA2 mutations in induced pluripotent stem cells from two unrelated SPG46 patients and have thus created isogenic controls. After differentiation of these cells into cortical neurons, a cell type affected in GBA2-associated HSP, we will perform lipidomic analyses to address the following key topics:
- What are the consequences of GBA2 dysfunction on neuronal lipid composition? Which lipid metabolic pathways are mainly affected?
- Are changes observed in induced cortical neurons also present in patient biofluids?
- Are dysregulated lipid metabolic pathways amenable to pharmacological interventions? Paradigmatic compounds will be tested on cortical neurons for their potential to correct the GBA2-specific changes in lipid composition.