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Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains.
Ann Neurol 2012; 72(3):455-63AN

Abstract

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

INTERPRETATION

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.

Authors+Show Affiliations

Department of Clinical Neurosciences, University College London Institute of Neurology.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23034917

Citation

Gegg, Matthew E., et al. "Glucocerebrosidase Deficiency in Substantia Nigra of Parkinson Disease Brains." Annals of Neurology, vol. 72, no. 3, 2012, pp. 455-63.
Gegg ME, Burke D, Heales SJ, et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol. 2012;72(3):455-63.
Gegg, M. E., Burke, D., Heales, S. J., Cooper, J. M., Hardy, J., Wood, N. W., & Schapira, A. H. (2012). Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Annals of Neurology, 72(3), pp. 455-63. doi:10.1002/ana.23614.
Gegg ME, et al. Glucocerebrosidase Deficiency in Substantia Nigra of Parkinson Disease Brains. Ann Neurol. 2012;72(3):455-63. PubMed PMID: 23034917.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. AU - Gegg,Matthew E, AU - Burke,Derek, AU - Heales,Simon J R, AU - Cooper,J Mark, AU - Hardy,John, AU - Wood,Nicholas W, AU - Schapira,Anthony H V, PY - 2012/10/5/entrez PY - 2012/10/5/pubmed PY - 2012/12/15/medline SP - 455 EP - 63 JF - Annals of neurology JO - Ann. Neurol. VL - 72 IS - 3 N2 - OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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. SN - 1531-8249 UR - https://www.unboundmedicine.com/medline/citation/23034917/Glucocerebrosidase_deficiency_in_substantia_nigra_of_parkinson_disease_brains_ L2 - https://doi.org/10.1002/ana.23614 DB - PRIME DP - Unbound Medicine ER -