Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains
Article first published online: 2 OCT 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 3, pages 455–463, September 2012
How to Cite
Gegg, M. E., Burke, D., Heales, S. J. R., Cooper, J. M., Hardy, J., Wood, N. W. and Schapira, A. H. V. (2012), Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol., 72: 455–463. doi: 10.1002/ana.23614
- Issue published online: 2 OCT 2012
- Article first published online: 2 OCT 2012
- Accepted manuscript online: 14 APR 2012 08:24AM EST
- Manuscript Revised: 2 APR 2012
- Manuscript Accepted: 2 APR 2012
- Manuscript Received: 23 NOV 2011
- Wellcome Trust/Medical Research Council (MRC)
- Joint Call in Neurodegeneration award. Grant Number: (WT089698)
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. ANN NEUROL 2012;72:455–463.