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. 2015 Mar 27:10:15.
doi: 10.1186/s13024-015-0010-2.

Selective loss of glucocerebrosidase activity in sporadic Parkinson's disease and dementia with Lewy bodies

Davide Chiasserini  1 , Silvia Paciotti  2 , Paolo Eusebi  3   4 , Emanuele Persichetti  5 , Anna Tasegian  6 , Marzena Kurzawa-Akanbi  7   8 , Patrick F Chinnery  9   10 , Christopher M Morris  11 , Paolo Calabresi  12   13 , Lucilla Parnetti  14 , Tommaso Beccari  15
Affiliations

Selective loss of glucocerebrosidase activity in sporadic Parkinson's disease and dementia with Lewy bodies

Davide Chiasserini et al. Mol Neurodegener. .

Abstract

Background: Lysosomal dysfunction is thought to be a prominent feature in the pathogenetic events leading to Parkinson's disease (PD). This view is supported by the evidence that mutations in GBA gene, coding the lysosomal hydrolase β-glucocerebrosidase (GCase), are a common genetic risk factor for PD. Recently, GCase activity has been shown to be decreased in substantia nigra and in cerebrospinal fluid of patients diagnosed with PD or dementia with Lewy Bodies (DLB). Here we measured the activity of GCase and other endo-lysosomal enzymes in different brain regions (frontal cortex, caudate, hippocampus, substantia nigra, cerebellum) from PD (n = 26), DLB (n = 16) and age-matched control (n = 13) subjects, screened for GBA mutations. The relative changes in GCase gene expression in substantia nigra were also quantified by real-time PCR. The role of potential confounders (age, sex and post-mortem delay) was also determined.

Findings: Substantia nigra showed a high activity level for almost all the lysosomal enzymes assessed. GCase activity was significantly decreased in the caudate (-23%) and substantia nigra (-12%) of the PD group; the same trend was observed in DLB. In both groups, a decrease in GCase mRNA was documented in substantia nigra. No other lysosomal hydrolase defects were determined.

Conclusion: The high level of lysosomal enzymes activity observed in substantia nigra, together with the selective reduction of GCase in PD and DLB patients, further support the link between lysosomal dysfunction and PD pathogenesis, favoring the possible role of GCase as biomarker of synucleinopathy. Mapping the lysosomal enzyme activities across different brain areas can further contribute to the understanding of the role of lysosomal derangement in PD and other synucleinopathies.

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Figures

Figure 1
Figure 1
Lysosomal enzyme activities in human brain. a) Cluster analysis of lysosomal enzyme activities. Lysosomal specific activities were normalized with respect to their means and standard deviations, while patients were summarized using their respective diagnostic group; b) Boxplots of the GCase specific activity across different brain areas. In the table below the figure, the significant comparisons are reported according to the statistical model used; c) mRNA levels of GBA gene. 2-ΔCT values normalized by housekeeping genes GAPDH and SDHA. *p < 0.05 using Wilcoxon two groups test and nonparametric ANCOVA model with adjustment for post mortem delay.
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