Mitochondrial and lysosomal dysfunction in GBA2-associated Hereditary Spastic Paraplegia

Hereditary Spastic Paraplegias (HSPs) are a large group of neurodegenerative diseases that share common symptoms like lower limb stiffness and spasticity. More than 70 genes whose mutations cause HSPs have been identified and they are involved in different molecular mechanisms, such as lipid metabolism, mitochondrial function, and endo-lysosomal system regulation. Among them, GBA2 gene, encoding the non-lysosomal glucocerebrosidase GBA2 has been associated with hereditary spastic paraplegia 46 (SPG46). GBA2 catalyzes the same reactions as GBA1 (the lysosomal glucosylceramidase), but in different cellular compartments: the hydrolysis of glucosylceramide (GlcCer) to glucose and ceramide and the transglucosylation of the glucose moiety to cholesterol to form glucosylcholesterol (GlcChol). GBA2 mutations can lead to an accumulation of GlcCer and a depletion of GlcChol, but the pathogenetic mechanism(s) that determine GBA2-HSP etiology are still unknown. Given the evidence from our unpublished data that GBA2-inhibited neurons display an increased calcium response to glutamate stimulation and given that there is an unclear correlation between GBA2 and the lysosomal GBA1, we hypothesized that mitochondria and lysosomes could play a role in the pathology. Thus, the aim of the project was to assess the effect of GBA2 inhibition on mitochondria and lysosomes using two experimental models: HEK293 cells and mice cerebellar neurons upon GBA2 inhibition.