Dataset Information

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, ?-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 ?-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.

SUBMITTER: Gegg ME

PROVIDER: S-EPMC3638323 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Publications

Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains.

Gegg Matthew E ME Burke Derek D Heales Simon J R SJ Cooper J Mark JM Hardy John J Wood Nicholas W NW Schapira Anthony H V AH

Annals of neurology 20120901 3

<h4>Objective</h4>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.<h4>Methods</h4>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 expr ...[more]

PMID: 23034917

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Project description:Background Motor symptoms in Parkinson disease (PD) have exhibited lateral asymmetry, suggesting asymmetric neuronal loss in the substantia nigra (SN). Diffusion MRI may be able to help confirm tissue microstructural alterations in the substantia nigra to probe for the presence of asymmetry. Purpose To investigate lateral asymmetry in the SN of patients with PD by using diffusion MRI with both Gaussian and non-Gaussian models. Materials and Methods In this cross-sectional study conducted from March 2015 to March 2017, 27 participants with PD and 27 age-matched healthy control (HC) participants, all right handed, underwent MRI at 3.0 T. High-spatial-resolution diffusion images were acquired with a reduced field of view by using seven b values up to 3000 sec/mm2. A continuous-time random-walk (CTRW) non-Gaussian diffusion model was used to produce anomalous diffusion coefficient (Dm) and temporal (α) and spatial (β) diffusion heterogeneity indexes followed by a Gaussian diffusion model to yield an apparent diffusion coefficient (ADC). Individual or linear combinations of diffusion parameters in the SN were unilaterally and bilaterally compared between the PD and HC groups. Results In the bilateral comparison between the PD and HC groups, differences were observed in β (0.67 ± 0.06 [standard deviation] vs 0.64 ± 0.04, respectively; P = .016), ADC (0.48 μm2/msec ± 0.08 vs 0.53 μm2/msec ± 0.06, respectively; P = .03), and the combination of CTRW parameters (P = .02). In the unilateral comparison, differences were observed in all diffusion parameters on the left SN (P < .03), but not on the right (P > .20). In a receiver operating characteristic (ROC) analysis to delineate left SN abnormality in PD, the combination of Dm, α, and β produced the best sensitivity (sensitivity, 0.78); the combination of Dm and β produced the best specificity (specificity, 0.85); and the combination of α and β produced the largest area under the ROC curve (area under the ROC curve, 0.73). Conclusion These results suggest that quantitative diffusion MRI is sensitive to brain tissue changes in participants with Parkinson disease and provide evidence of substantia nigra lateral asymmetry in this disease. © RSNA, 2019 Online supplemental material is available for this article.

Dataset Information

Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains.

Objective

Methods

Results

Interpretation

Publications

Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains.

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