Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains

TLDR

Mutations in the glucocerebrosidase gene (GBA) are a major genetic risk factor for Parkinson disease, and biochemical alterations in GCase expression may contribute to disease pathogenesis. The study aimed to assess glucocerebrosidase enzymatic activity in Parkinson disease brains with heterozygous GBA mutations compared to sporadic PD brains. GCase activity was quantified by a fluorescent assay across multiple brain regions, while protein expression of GCase and other lysosomal proteins was evaluated by western blotting, and in vitro experiments examined the interaction of GCase with α‑synuclein and mitochondrial function. GCase activity was markedly reduced in Parkinson disease brains, especially in the substantia nigra (58% decrease in GBA‑mutant cases and 33% in sporadic cases), accompanied by lower protein levels and activation of the unfolded protein response, indicating that both catalytic loss and protein depletion underlie the deficiency, most pronounced in the substantia nigra.

Abstract

Mutations in the glucocerebrosidase gene (GBA) represent a significant risk factor for developing Parkinson disease (PD). We investigated the enzymatic activity of glucocerebrosidase (GCase) in PD brains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains.GCase activity was measured using a fluorescent assay in cerebellum, frontal cortex, putamen, amygdala, and substantia nigra of PD+GBA (n = 9-14) and sporadic PD brains (n = 12-14). Protein expression of GCase and other lysosomal proteins was determined by western blotting. The relation between GCase, α-synuclein, and mitochondria function was also investigated in vitro.A significant decrease in GCase activity was observed in all PD+GBA brain areas except the frontal cortex. The greatest deficiency was in the substantia nigra (58% decrease; p < 0.01). GCase activity was also significantly decreased in the substantia nigra (33% decrease; p < 0.05) and cerebellum (24% decrease; p < 0.05) of sporadic PD brains. GCase protein expression was lower in PD+GBA and PD brains, whereas increased C/EBP homologous protein and binding immunoglobulin protein levels indicated that the unfolded protein response was activated. Elevated α-synuclein levels or PTEN-induced putative kinase 1 deficiency in cultured cells had a significant effect on GCase protein levels.GCase deficiency in PD brains with GBA mutations is a combination of decreased catalytic activity and reduced protein levels. This is most pronounced in the substantia nigra. Biochemical changes involved in PD pathogenesis affect wild-type GCase protein expression in vitro, and these could be contributing factors to the GCase deficiency observed in sporadic PD brains.