title: Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains.
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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Clinical Neurosciences, University College London Institute of Neurology.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Gegg
authors.forename: Derek
authors.initials: D
authors.lastname: Burke
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cooper
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D005776:Gaucher Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation; D009447:Neuroblastoma; D010300:Parkinson Disease / Q000150:complications / Q000473:pathology*; D011494:Protein Kinases / Q000172:deficiency; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D005962:Glucosylceramidase; D011494:Protein Kinases; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase